Drug-delivery pumps and methods of manufacture

ABSTRACT

Embodiments of method of manufacturing an implantable pump, including providing an upper layer comprising a dome structure for housing a drug chamber and a cannula in fluid communication with the drug chamber, providing a middle deflection layer adjacent the drug chamber, providing a bottom layer comprising electrolysis electrodes, and bonding the upper layer, middle deflection layer, and bottom layer to form the pump.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to, and the benefit of, U.S.Provisional Patent Application Nos. 61/051,422, filed on May 8, 2008;61/197,817, filed on Oct. 30, 2008; 61/197,750, filed on Oct. 30, 2008;61/201,197, filed on Dec. 8, 2008; 61/198,144, filed on Nov. 3, 2008;and 61/150,515, filed on Feb. 6, 2009, the entire disclosures of whichare hereby incorporated herein by reference.

TECHNICAL FIELD

In various embodiments, the invention relates to the delivery oftherapeutic fluids, and more particularly to implantable systems andmethods for delivering therapeutic fluids to a treatment site within abody.

BACKGROUND

Medical treatment often requires the administration of a therapeuticagent (e.g., medicament, drugs, etc.) to a particular part of apatient's body. As patients live longer and are diagnosed with chronicand/or debilitating ailments, the likely result will be an increasedneed to place even more protein therapeutics, small-molecule drugs, andother medications into targeted areas throughout the patient's body.Some maladies, however, are difficult to treat with currently availabletherapies and/or require administration of drugs to anatomical regionsto which access is difficult to achieve.

A patient's eye is a prime example of a difficult-to-reach anatomicalregion, and many vision-threatening diseases, including retinitispigmentosa, age-related macular degeneration (AMD), diabeticretinopathy, and glaucoma, are difficult to treat with many of thecurrently available therapies. For example, oral medications can havesystemic side effects; topical applications may sting and engender poorpatient compliance; injections generally require a medical visit, can bepainful, and risk infection; and sustained-release implants musttypically be removed after their supply is exhausted (and generallyoffer limited ability to change the dose in response to the clinicalpicture).

Another example is cancer, such as breast cancer or meningiomas, wherelarge doses of highly toxic chemotherapies, such as rapamycin,bevacizumab (e.g., Avastin), or irinotecan (CPT-11), are typicallyadministered to the patient intravenously, which may result in numerousundesired side effects outside the targeted area. Other examples ofdifficult-to-reach anatomical regions for drug delivery include theknee, where drugs often have difficulty penetrating the avascularcartilage tissue for diseases such as osteoarthritis, the brain, and thespine.

Methods that use an implantable drug delivery system, which may includea refillable drug reservoir, a cannula for delivering the drug, etc.,generally allow for controlled delivery of pharmaceutical solutions to aspecified target. This approach can minimize the surgical incisionneeded for implantation and typically avoids future or repeated invasivesurgery or procedures. In ocular applications, implantable devicessometimes utilize a passive mechanism for drug delivery, in which drugis pumped out when, for example, a finger is pressed on the drugreservoir. This may, however, render the control of the administereddrug dosage problematic. In addition, the fabrication of such devicesmay require cumbersome and expensive hand-assembling work.Electrolysis-driven implantable MEMS drug-delivery devices are alsoknown, but may be rigid and therefore risk damage to the site ofimplantation (particularly where delicate (e.g., ocular) tissue isinvolved).

A need exists, therefore, for improved implantable drug-delivery devicesand methods of manufacture.

SUMMARY OF THE INVENTION

In various embodiments, the present invention relates to improvedsystems and methods for delivering a drug to a target location within abody, and methods of manufacturing systems for drug delivery. Pumps inaccordance with the invention may be shaped to conform to a particularanatomical region, and may be sized for any of a variety of anatomicalsites. They can be made of biocompatible materials (e.g., parylene) toenhance patient comfort and safety.

Some embodiments of the invention relate to electrolytic pumps and, inparticular, designs and features that relieve pressure buildup duringoperation, thereby avoiding needless power loss and long actuationtimes. Particular implementations can include, for example, osmoticmembranes or perforated shells; indeed, an osmotic mechanism can be usedto drive pump operation instead of (or in addition to) relievinginternal pressure.

Some embodiments of the invention relate to data telemetry and wirelesspowering and programming of an implanted pump, and to particularoperative and control components that extend device capabilities. Forexample, external communication with (and/or wireless recharging of) aninternally implanted pump may take place using a wearable telemetryand/or charging device implemented, for example, in eyeglasses or an eyepatch for the eye, a headband for the brain or a kneebrace for the knee;when the user wears the device as intended, optimal alignment betweencommunicating components may be enforced. Telemetry may beelectromagnetic or, in some implementations, optical.

Some embodiments of the invention relate to efficient powering of animplantable pump, and the use of redundant power sources for safetypurposes. For example, a redundant battery may take over pump operationupon failure of the main battery, or may instead execute a controlledshutdown of the pump and/or issuance of an alert. The alert may includean audible signal, a vibration, an optical signal, a shock, and/or atranscutaneous neural stimulation.

Some embodiments of the invention relate to convenient, automatedmanufacture of implantable pumps as described herein. Embodiments of theinvention also facilitate convenient sterilization of implantable pumpswithout damage to vulnerable components thereof.

Various aspects of the invention relate to manufacture of implantablepumps. One such method includes providing an upper layer comprising adome structure for housing a drug chamber and a cannula in fluidcommunication with the drug chamber, providing a middle deflection layeradjacent the drug chamber, providing a bottom layer comprisingelectrolysis electrodes, and thermally bonding the upper layer, middledeflection layer, and bottom layer to form the pump.

In one embodiment, the method includes forming the drug chamber betweenthe upper layer and the middle deflection layer after thermal bondingand/or forming the electrolysis chamber between the middle deflectionlayer and bottom layer after thermal bonding. A casing may be providedto at least partially surrounding the pump. The casing may include aperforated shell located above at least a portion of the upper layer.

The method may further include retaining an opening between layersduring the thermal bonding step to provide a fill port for at least oneof the drug chamber or the electrolysis chamber, filling at least one ofthe drug chamber or the electrolysis chamber with a fluid through theopening and sealing the opening. The opening may be thermally sealed. Atleast one fill port may be provided in fluid communication with of theelectrolysis chamber and/or the drug chamber. In one embodiment, themethod includes aligning the upper layer, the middle deflection layer,and the bottom layer on a jig assembly prior to thermal bonding. Thealigning step and/or the bonding step may be at least partiallyautomated.

The method may further include inserting tubing between at least twoabutting layers during the alignment process and before thermal bondingoccurs to provide a fill port for a chamber formed between the twoabutting layers after thermal bonding, filling the chamber with a fluidthrough the tubing, and removing the tubing after filling and thermallysealing the hole left by the removed tubing.

The upper layer, the middle layer, and/or the bottom layer may be formedby a lithographic process. The lithographic process may includesequentially layering layers of a construction material and aphotoresist material, etching at least one of the construction materialsand a photoresist material to provide a required shape, and subjectingthe layers to photoresist stripper, thereby removing the photoresistmaterial and leaving the shaped construction material in place. Theupper layer, the middle layer, and/or the bottom layer may alternativelybe formed by a molding process. The upper layer, middle layer, and/orbottom layer may include or consists essentially of parylene and/or acomposite material (e.g. a parylene-metal-parylene combination includingplatinum and parylene).

In one embodiment, the upper layer is formed according to stepsincluding forming a hole in a wall of the dome structure and bonding aproximal portion of the cannula to the wall using a biocompatibleadhesive. The hole may be created through etching and/or insertion of aheated metal probe. The dome structure may be manufactured by providinga mold having a domed shape, conformably coating a layer of material onthe mold, and after the material has set, peeling the resulting domestructure from the mold. Alternatively, the dome structure may bemanufactured according to steps including providing a first mold elementhaving a domed shape, providing a second complementary mold element,conformably disposing a sheet of material between the first mold elementand the second complementary mold element, heating the first moldelement, the second complementary mold element, and the conformed sheetof material to anneal the sheet of material, and removing the first moldelement and second complementary mold element from the annealed sheet ofmaterial.

The cannula may be manufactured according to steps including coating afirst photoresist layer onto a silicon substrate as a sacrificial layer,depositing a first parylene layer onto the photoresist layer to form abottom surface of the cannula, creating a through hole in the firstparylene layer, and coating a second photoresist layer over the firstparylene layer. A second parylene layer may then be deposited on thesecond photoresist layer, so that the second parylene layer forms a topand a side of the cannula. Then the first and second parylene layers arepatterned to form a cannula shape, and the first and second photoresistlayers are removed, thereby leaving the formed cannula. The patterningstep may include reactive-ion etching with a photoresist material usedas an etching mask, and/or patterning the first parylene layer andsecond parylene layer in a RIE oxygen plasma using a photoresist mask.At least one of the coating steps may include spin-coating.

The cannula may be integrated with the dome structure by forming a holein an edge portion of the dome structure, inserting a proximal portionof the cannula into the hole, and bonding the proximal portion of thecannula a wall of the hole formed in the dome structure. In anotherembodiment, the dome structure is integrally formed with the cannula bysteps including: (i) coating a first photoresist layer onto a siliconsubstrate as a sacrificial layer; (ii) depositing a first parylene layercomprising a first parylene sheet onto the photoresist layer, the firstparylene sheet forming the dome structure; (iii) coating a secondphotoresist layer onto the first parylene layer; (iv) opening a bondingarea in the second photoresist layer by lithography; (v) depositing asecond parylene layer on the second photoresist layer, wherein thesecond parylene layer forms the bottom of the cannula and bonds to thefirst parylene layer at the bonding area; (vi) creating a through holein the first parylene layer; (vii) coating a third photoresist layeronto the second parylene layer; (viii) depositing a third parylene layeron the third photoresist layer, the third parylene layer forming a topand a side of the cannula; (ix) patterning the second parylene layer andthird parylene layer to form a cannula shape; (x) removing the first,second, and third photoresist layers, thereby leaving the formed cannulabonded to the flat parylene sheet; and (xi) molding the flat parylenesheet to form the dome structure. The patterning step may includereactive-ion etching with a photoresist material used as an etching maskand/or patterning the first parylene layer and second parylene layer ina RIE oxygen plasma using a photoresist mask. At least one of thecoating steps may include spin-coating.

The method may further include integrating a check valve, a pressuresensor, a chemical sensor, and/or a flow sensor into the pump and, forexample, into the cannula. In one embodiment, the an upper layer withintegrated check valve and sensor (e.g. pressure, chemical, and/or flowsensor) is integrally formed with the cannula according to stepsincluding: (i) coating a first photoresist layer onto a siliconsubstrate as a sacrificial layer; (ii) depositing a first parylene layercomprising a flat parylene sheet onto the photoresist layer to form abottom surface of the cannula; (iii) patterning a layer of firstmaterial on the first parylene layer to form at least one check valvering; (iv) depositing a layer of a second material on the first parylenelayer to form a flow sensor; (vi) patterning the first parylene layer toform a cannula shape; (vii) coating a second photoresist layer over thefirst parylene layer; (viii) depositing a second parylene layer over thesecond photoresist layer, wherein the second parylene layer forms acheck valve diaphragm and a protective layer for the flow sensor; (ix)patterning tethers for the check valve; (x) patterning the secondphotoresist layer to form a check valve chamber and a micro-channel;(xi) depositing a third parylene layer to form a top and sides of aparylene channel; (xii) patterning the cannula channel by etchingthrough the first, second, and third parylene layers; (xiii) removingthe photoresist layers by subjection to photoresist stripper, therebyleaving the formed channel with check valve and flow sensor; and (xiv)molding the flat parylene sheet to form the dome structure. The firstmaterial and/or the second material may include or consist essentiallyof a metal. The metal may be selected from the group consisting ofCr/Au, Ti/Au, and Pt.

In one embodiment, the middle deflection layer includes a corrugateddiaphragm, which may be formed according to steps including coating afirst photoresist layer onto a silicon substrate, etching the siliconsubstrate using the first photoresist layer as a mask, removing thefirst photoresist layer, thereby leaving a mold formed by the siliconsubstrate, coating a parylene layer on the silicon substrate and, afterthe parylene layer has set, releasing the parylene layer from thesilicon substrate, thereby forming the corrugated diaphragm. Asubstantially rigid spacer comprising a refill hole may be positionedbetween the middle deflection layer and the bottom layer.

The middle deflection layer may include a bellows structure. The bellowsstructure may be formed according to steps including: (i) coating afirst photoresist layer onto a silicon substrate as a sacrificial layer;(ii) depositing a first parylene layer onto the first photoresist layerto form a first layer of the bellows structure; (iii) coating a secondphotoresist layer over the first parylene layer; (iv) opening a bondingarea in the second photoresist layer by lithography; (v) depositing asecond parylene layer onto the second photoresist layer to form a secondlayer of the bellows structure, wherein the second parylene layer bondsto the first parylene layer at the bonding area; (vi) patterning thefirst and second parylene layers; (vii) coating a third photoresistlayer onto the second parylene layer; (viii) depositing a third parylenelayer onto the third photoresist layer to form a third layer of thebellows structure; (ix) patterning the bellows structure by etchingthrough the second and third parylene layers, and (x) removing thephotoresist layers by subjection to photoresist stripper, therebyleaving the parylene bellows structure.

In one embodiment, the bottom layer is formed according to stepsincluding coating a first photoresist layer onto a silicon substrate asa sacrificial layer, depositing a first parylene layer onto the firstphotoresist layer to form a first layer of the bottom layer, depositinga metal electrode layer on the first parylene layer, depositing a secondparylene layer over the metal electrode layer, etching the secondparylene layers to expose at least a portion of the electrode, andremoving the photoresist layers by subjection to photoresist stripper,thereby leaving the bottom layer. The metal electrode layer may bedeposited by E-beam evaporation and patterned by a lift-off process oretching process. The etching step may include RIE oxygen plasma etchingmasked by a photoresist mask. The bottom layer may be annealed toimprove the adhesion between the parylene layers and the metal electrodelayer. The metal electrode layer may include or consist essentially ofplatinum.

Another aspect of the invention includes a method of manufacturing animplantable pump. The method includes providing an upper layercomprising a dome structure for housing a drug chamber and a cannula influid communication with the drug chamber, providing a middle deflectionlayer adjacent the drug chamber, providing a bottom layer comprising apermeable membrane, and thermally bonding the upper layer, middledeflection layer, and bottom layer to form the pump.

The bottom layer may be formed by coating a first photoresist layer ontoa silicon substrate as a sacrificial layer, depositing a first parylenelayer onto the first photoresist layer to form a first layer of thebottom layer, depositing a second photoresist layer over the firstparylene layer and patterning the second photoresist layer, depositing asecond parylene layer over the second photoresist layer, etching thesecond parylene layer, and removing the photoresist layers, therebyleaving the bottom layer. Portions of the bottom layer including onlythe first parylene layer may be at least partially permeable, and/orportions of the bottom layer including both the first and secondparylene layers may be substantially impermeable.

Another aspect of the invention includes a method of manufacturing adrug chamber for an implantable electrolytic pump. The method includes:(i) coating a first photoresist layer onto a silicon substrate as asacrificial layer; (ii) depositing a first parylene layer onto the firstphotoresist layer to form a first layer of the pump; (iii) coating asecond photoresist layer over the first parylene layer; (iv)lithographically patterning the second photoresist layer by differentialexposure to create a plurality of concentric ridges; (v) depositing asecond parylene layer onto the second photoresist layer; (vi) patterningthe first and second parylene layers; and (vii) removing the photoresistlayers, thereby leaving the drug chamber.

Another aspect of the invention pertains to pump sterilization. In oneembodiment, a method of sterilization is performed on an implantableelectrolytic pump having an electrolysis chamber, a drug chamber, and asealed enclosure containing electrical components. The method includes,before assembly, sterilizing the electrolysis chamber and drug chamber,attaching the electrolysis chamber and drug chamber to the sealedenclosure to form the sealed chambers thereover, and sterilizing aninterior of the electrolysis chamber and drug chamber. The methodfurther includes filling the electrolysis chamber with at least oneworking fluid, filling the drug chamber with at least one drug, andsubjecting the implantable electrolytic pump to a final sterilization.The electrolysis chamber and drug chamber may be sterilized, prior toassembly, by radiational sterilization and/or by exposure to asterilizing gas. The sterilizing gas may include or consists essentiallyof ethylene oxide.

In one embodiment, the interiors of the electrolysis chamber and drugchamber are sterilized, after assembly, by introduction of a sterilizinggas. The sterilizing gas may be introduced through refill portsassociated with one or both of the electrolysis chamber and the drugchamber. If necessary, prior to introduction of the sterilizing gas, theinteriors of the electrolysis chamber and the drug chamber can besubjected to a negative pressure through their refill ports. The finalsterilization of the pump may include exposing the pump to a sterilizinggas, which may include or consists essentially of ethylene oxide. In oneembodiment, the pump may include a reservoir wall mounted over thedrug-reservoir membrane. The pump may be hermetically packaged in itssterilized form.

Yet another aspect of the invention includes a method of sterilizing asealed-chamber device during assembly thereof. The method includes thesteps of sterilizing a pair of heat-sensitive boundary membranes in amanner that does not damage them, attaching the sterilized membranes toa support to form sealed chambers each bounded by at least one of themembranes, such that a refill port fluidly communicates with eachchamber. The chambers are sterilized by introducing a sterilizing gastherein via the refill ports, and replacing the gas in each of thechambers with a working fluid via the refill ports. The membranes may besterilized by exposure to radiation and/or a sterilizing gas (e.g.,ethylene oxide) prior to attachment. The method may further includesterilizing the device following the replacement step by exposure to asterilizing gas.

These and other objects, along with advantages and features of thepresent invention herein disclosed, will become more apparent throughreference to the following description, the accompanying drawings, andthe claims. Furthermore, it is to be understood that the features of thevarious embodiments described herein are not mutually exclusive and canexist in various combinations and permutations.

These and other objects, along with advantages and features ofembodiments of the present invention herein disclosed, will become moreapparent through reference to the following description, theaccompanying drawings, and the claims. Furthermore, it is to beunderstood that the features of the various embodiments described hereinare not mutually exclusive and can exist in various combinations andpermutations.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, like reference characters generally refer to the sameparts throughout the different views. Also, the drawings are notnecessarily to scale, emphasis instead generally being placed uponillustrating the principles of the invention. In the followingdescription, various embodiments of the present invention are describedwith reference to the following drawings, in which:

FIG. 1 shows a schematic sectional view of a drug-delivery pumpimplanted in a patient's eye, in accordance with one embodiment of theinvention;

FIG. 2 shows a schematic sectional view of the pump of FIG. 1 with acorrugated membrane;

FIG. 3 shows a schematic sectional view of the pump of FIG. 1 with themembrane expanded;

FIG. 4A shows another schematic sectional view of the pump of FIG. 1implanted in a patient's eye;

FIG. 4B shows a schematic sectional view of another drug-delivery pumpimplanted in a patient's eye, in accordance with one embodiment of theinvention;

FIG. 5 shows a schematic plan view of another implantable drug-deliverypump, in accordance with one embodiment of the invention;

FIG. 6 shows a schematic perspective view of another implantabledrug-delivery pump, in accordance with one embodiment of the invention;

FIG. 7 shows an exploded schematic perspective view of the pump of FIG.6;

FIG. 8 shows a schematic sectional view of an implantable drug-deliverypump having a perforated shell, in accordance with one embodiment of theinvention;

FIG. 9 shows a schematic sectional view of an osmosis-driven implantabledrug-delivery pump, in accordance with one embodiment of the invention;

FIG. 10 shows a schematic sectional view of an implantable drug-deliverypump having an osmosis chamber, in accordance with one embodiment of theinvention;

FIG. 11 shows a schematic sectional view of the pump of FIG. 10 duringactivation of electrolysis electrodes;

FIG. 12 shows a schematic sectional view of the pump of FIG. 10 afterde-activation of the electrolysis electrodes;

FIG. 13 shows a schematic perspective view of a shell for a pump, inaccordance with one embodiment of the invention;

FIG. 14 shows an elevational view of the pump of FIG. 13;

FIG. 15 shows a perspective view of a shell for a pump with sutureeyelets, in accordance with one embodiment of the invention;

FIG. 16 shows a schematic side view of the pump of FIG. 15;

FIG. 17 shows another schematic perspective view of the pump of FIG. 15;

FIG. 18 shows a schematic perspective view of a shell for a pump withsuture eyelets and a coil, in accordance with one embodiment of theinvention;

FIG. 19 shows a schematic side view of the pump of FIG. 18;

FIG. 20 shows a schematic plan view of another shell for a pump, inaccordance with one embodiment of the invention;

FIG. 21 is a schematic plan view of the pump of FIG. 20 with the cannularedirected;

FIG. 22 shows a schematic side view of the pump of FIG. 20;

FIG. 23 shows another schematic side view of the pump of FIG. 20;

FIG. 24 shows a sectional schematic perspective view of a pump encasedwithin a shell, in accordance with one embodiment of the invention;

FIG. 25A-25F show steps in the fabrication of a top layer of a drugchamber in accordance with an embodiment of the invention;

FIG. 26 shows a perspective view of a top layer of a drug chamber withintegrated cannula as formed using the process of FIGS. 25A-25F;

FIG. 27A-27F show steps in the fabrication of another top layer of adrug chamber in accordance with an embodiment of the invention;

FIG. 28 shows a perspective view of a cannula being integrated with atop layer of a drug chamber using the process of FIGS. 27A-27F;

FIGS. 29A-29H show steps in the fabrication of another top layer of adrug chamber with integrated cannula in accordance with an embodiment ofthe invention;

FIG. 30 shows a perspective sectional view a check valve in accordancewith one embodiment of the invention;

FIGS. 31A-31J show steps in the fabrication of a cannula with integratedcheck valve and sensor in accordance with an embodiment of theinvention;

FIG. 32A shows a schematic plan view of a cannula incorporating a checkvalve and flow sensors;

FIG. 32B is an enlarged schematic plan view of the check valve shown inFIG. 32A;

FIG. 32C is a front sectional view of the check valve shown in FIG. 32B;

FIGS. 33A-33E show steps in the fabrication of a middle diaphragm layerof a pump having corrugations in accordance with an embodiment of theinvention;

FIGS. 34A-34H show steps in the fabrication of a middle diaphragm layerof a pump having bellows folds in accordance with an embodiment of theinvention;

FIGS. 35A-35E show steps in the fabrication of a bottom layer of a drugchamber including electrolysis electrodes in accordance with anembodiment of the invention;

FIGS. 36A-36E show steps in the fabrication of an osmosis chamber for apump in accordance with an embodiment of the invention;

FIG. 37 shows steps in the fabrication of an electrolysis chamber for apump in accordance with an embodiment of the invention;

FIG. 38 shows steps in the fabrication of a corrugated diaphragm for apump in accordance with an embodiment of the invention;

FIG. 39 shows steps in the fabrication of a cannula with integratedcheck valve and flow sensor in accordance with an embodiment of theinvention;

FIG. 40 is a schematic elevation of a modified cannula as fabricatedusing the process of FIG. 39; and

FIG. 41 is a schematic plan view of a glaucoma drainage device withintegrated drug pump, in accordance with one embodiment of theinvention.

DESCRIPTION

In general, embodiments of the present invention relate toelectrolysis-actuated, implantable drug-delivery pumps such as, but notlimited to, pumps based on micro-electro-mechanical systems (“MEMS”).Devices in accordance with the invention may, in some embodiments, bemonolithically microfabricated on multiple polymer layers. Parylene (apolymer of p-xylene) or other biocompatible materials may be employed toachieve an active device with full biocompatibility. For example, a drugreservoir, electrolysis chamber, cannula, check valve, and/or suturestructure of an implantable drug-delivery pump may each be manufactured,at least in part, from parylene. The implantable drug-delivery pump maybe used for the delivery of, for example, fluid (e.g., a drug in liquidform), cells, biologics, and/or a suspension of inorganic and/or organicparticles into the body of human or animal subjects.

In various embodiments of the invention, components, such aselectrolysis electrodes, an application specific integrated circuit(“ASIC”) or standard microcontroller chip, a battery, a coil for powerreception and two-way data transmission, flow, chemical, and pressuresensors, etc., may be embedded and integrated within the drug-deliverydevice and, for example, within parylene films incorporated into thedevice. In one embodiment, the device is flexible and easy to fit into aprotective shell having an optimized three-dimensional (3D) implantationgeometry.

One or more portions of the implantable pump may be manufactured from afilm of biocompatible material such as, but not limited to, parylene(e.g., parylene C). Parylene films may be formed from a pure molecularprecursor (a monomer vapor), and generally have no contaminatinginclusions, do not “outgas,” and form effective barriers against thepassage of contaminants to both the patient's body and the surroundingenvironment. The parylene films may generally be relatively thin andpinhole-free, non-liquid (no meniscus effects), produce no cure forces(applied at room temperature), and contain substantially no additives(catalysts, plasticizers, solvents). Parylene films may also provide asuitable barrier (against moisture, fluids, and gases), be inert (i.e.,insoluble in most solvents), lubricious, highly dielectric,biocompatible and biostable, sterilization-tolerant, and compatible withmost vacuum-stable materials (such as, but not limited to, silicon,plastics, metals, ceramics, fabrics, paper, and granular materials). Inan alternative embodiment, other biocompatible, water-resistantpolymers, such as, but not limited to, polydimethylsiloxane (PDMS),polyvinylidene fluoride (PVDF), and/or various piezoelectric polymers,can be used in place of, or in addition to, parylene films. In a furtherembodiment, biocompatible composite materials (e.g. aparylene-metal-parylene combination including platinum and parylene) maybe used in the diaphragm in place of, or in addition to, parylene and/orother biocompatible polymers.

Embodiments of the invention may be used to deliver a measured drugdosage to a treatments site within a number of locations within a body,such as, but not limited to, the eye, the brain, or the knee, Having adrug pump to dose the brain's parenchyma directly, for example, may behelpful in treating diseases such as Parkinson's Disease, Alzheimer'sDisease, cancer, stroke recovery and hydrocephalys. In one exemplaryembodiment, a pump may be implanted in the sub-arachnoid space of thebrain to provide chemotherapy or to provide another type of treatmentfor the brain, or near a tumor in any portion of the patient's body toprovide chemotherapy, or in a pancreas that does not respond well toglucose to provide agents (e.g., proteins, viral vectors, etc.) thatwill trigger insulin release, or elsewhere. Similarly, using animplantable pump to inject one or more drugs, such asanti-inflammatories (e.g. steroids, S-adenosylmethionine), hyaluronicacid, amino acids (e.g. calcitonin), directly to tissues within theknee, can help treat tissues such as cartilage which is known to have avery poor vascular supply. The pump may also be useful in treating otherareas of the body, such as the spine, to deliver pain medications (e.g.fentynl, morphine) and/or anti-inflammatories, where standard therapieshave been expensive or ineffective.

An exemplary drug-delivery pump, implanted within a patient's eye, isshown in FIG. 1. In this embodiment, the implantable MEMS drug-deliverypump 100 includes a pair of chambers 130, 140 (e.g., parylene envelopes)and a cannula 120. The top chamber 130 defines a drug reservoir thatcontains one or more drugs to be administered in liquid form, and thebottom chamber 140 contains a fluid (e.g., and electrolytic fluid)which, when subjected to electrolysis, evolves a gas including one ormore gaseous products (e.g. in one embodiment, electrolysis of the fluidwithin the electrolysis chamber produces two gases, H₂ and O₂). The twochambers are separated by a diaphragm 150. The diaphragm 150 may beelastic and/or may be corrugated to provide for expansion thereof inresponse to the phase-change of the fluid within the bottom chamber 140from a liquid to a gaseous state. The diaphragm 150 may be manufacturedfrom one or more parylene films and/or a composite material. Thechambers 130, 140 may be positioned within a shaped protective casing orshell 160 made of a relatively rigid biocompatible material (e.g.,medical-grade polypropylene, a metal, and/or a biocompatible plastic).The shell 160 provides a hard surface against which an outer wall 110 ofthe drug reservoir chamber 130 exerts pressure and which protects thepump from inadvertent external forces. The shell 160 may include asolid, perforated or non-perforated biocompatible material coated inparylene. Control circuitry 170, including, for example, a battery andan induction coil for power and data transmission, are embedded underthe bottom chamber 140 (e.g., between the bottom wall 180 of the bottomelectrolysis chamber 140 and the floor of the shell 160). In oneembodiment, the control circuitry 170 is embedded within a protectiveencapsulation 175 such as, but not limited to, a silicon and/or paryleneencapsulation. The control circuitry 170 provides power to one or moreelectrolysis electrodes 240 positioned within the bottom chamber 140,and may be secured to the electrolysis electrodes 240 by a material suchas, but not limited to, a conductive epoxy including a biocompatiblematerial (e.g. gold or silver). The electrolysis electrodes 240 may beformed on or within a parylene film forming the bottom surface of theelectrolysis chamber 140. An adhesion layer (e.g. including orconsisting of titanium) may be used to adhere the electrolysiselectrodes 240 to a bottom surface of the electrolysis chamber 140.Alternatively, the bottom surface of the electrolysis chamber 140 towhich the electrolysis electrodes 240 are coupled, or imbedded within,may include a substrate formed from a material including, but notlimited to, alumina, zirconium oxide, and/or sapphire. Activation ofthese electrolysis electrodes 240 produces a phase change in theelectrolytic fluid within the bottom chamber 140 by evolving the fluidfrom a liquid to a gaseous state (i.e. generating a gas throughelectrolysis).

The cannula 120 connects the drug chamber 130 with a treatment site 190.A check valve 200, one or more flow sensors (not shown), and/or one ormore chemical or pressure sensors (also not shown) may be positionedwithin the cannula 120 to control and/or monitor the flow of drug fromthe drug chamber 130, through the cannula 120, and into the treatmentsite 190. Check valves 200 may, for example, prevent leakage of a drugfrom the drug chamber 130 when the electrolysis electrodes 240 are notactivated and/or during a refilling process and/or prevent backwardfluid flow through the cannula into the drug chamber 130. The treatmentsite may be an eye 210 of a patient, or may be any other target bodyportion. For example, the pump 100 may be implanted in the sub-arachnoidspace of the brain to provide chemotherapy or to provide another type oftreatment for the brain, or near a tumor in any portion of the patient'sbody to provide chemotherapy, or in a pancreas that does not respondwell to glucose to provide agents (e.g., proteins, viral vectors, etc.)that will trigger insulin release, or elsewhere.

One or more flow sensors, such as, but not limited to, those based uponthermal effects, time-of-flight, and/or pressure, may be inserted at anyposition along the length of the cannula 120 to monitor the flow ofdrug—and thereby enable the measurement of drug volume—through thecannula 120. Alternatively or in addition, a pressure sensor may beintegrated at the distal end of the cannula 120 in order to measurepressure at the site of administration 190 (e.g., the intravitrealchamber, shoulder capsule, knee capsule, cerebral ventricals, spinalcanal, etc.). Further pressure sensors may be integrated along thecannula 120 or placed elsewhere in the pump 100, such as, but notlimited to, within the drug chamber 130 and/or bottom electrolysischamber 140. Chemical sensors may be used, for example, to monitor oneor more chemical compositions within a treatment site (e.g. monitoringthe brains cerebral spinal fluid (CSF) for chemicals such as osmolarity,sugar and infection). The sensors may provide enough feedback to thecontrol circuitry 170 to allow the flow of drugs to be metered by aclosed-loop control process. For example, increased pressure exerted bythe surrounding areas may cause the increased flow of drug from the pump100 to maintain the closed-loop control.

In one embodiment, as illustrated in FIG. 2, the diaphragm 150 includesa plurality of corrugations 230. When current is supplied to theelectrolysis electrodes 240 by the circuitry 170, the electrolytic fluidwithin the bottom chamber 140 evolves into a gas. This phase changeincreases the volume of the bottom chamber 140, thereby expanding thediaphragm 150, as shown in FIG. 3, and forcing liquid out of the drugreservoir 130, through the cannula 120, and toward the treatment site190. When current to the electrolysis electrodes 240 is stopped, the gaswithin the bottom chamber 140 dissipates back into its liquid state, andthe diaphragm 150 of the electrolysis chamber recovers itsspace-efficient corrugations 230. The corrugations 230 permit a largedegree of membrane 150 expansion without sacrificing volume within thedrug reservoir 130 when the diaphragm 150 is relaxed. In one embodiment,the circuitry 170 provides an adjustable current or voltage to theelectrolysis electrodes 240 to adjustably control the expansion of thediaphragm 150 and therefore the flow rate of drug from the drug chamber130.

In an alternative embodiment, the diaphragm 150 includes a bellowsconfiguration and/or a highly elastic material in addition to, or inplace of, the corrugations 230. For example, as shown in FIG. 1, thesidewalls of the membrane 150 have folds 250 forming the bellowsstructure, so that the membrane 150 is substantially flat in itscollapsed configuration. In this embodiment, when the gas is formed inthe bottom chamber 140, the folds 250 open and the membrane 150 expands.As a result, the bellows structure 250 may achieve large diaphragmdeflections. It should be stressed that essentially any space-saving,expandable arrangement of folds may be utilized. The material of themembrane 150 for any of the embodiments described herein may include, orconsist essentially of, parylene and/or other suitable materials.

With reference now to FIGS. 4A and 4B, in one embodiment, one or morerefill ports 220 are placed in fluid communication with the drugreservoir 130. As illustrated in FIG. 4A, the refill port 220 may beassembled with the drug reservoir 130 and sealed by a sealant (e.g., abiocompatible epoxy) 225 both to the wall 110 defining the drugreservoir 130 and to the protective shell 160. Alternatively, asillustrated in FIG. 4B, a hole may be formed through the protectiveshell 160 and the refill port 220 featured therein. In still anotherembodiment, the refill port 220 may be formed elsewhere on the pump 100and be connected to the drug reservoir 130 through tubing. For example,the refill port 220 may be molded from biocompatible materials, coupledto a matching notch on a hermetic case 235 shown in FIG. 4B andconnected to the drug reservoir 130 through the tubing. In oneembodiment, the tubing is inserted through a fluid connection portformed in the wall 110 surrounding the drug reservoir 130 and bondedthereto by way of a biocompatible epoxy glue. In either case, the refillport 220 is in fluid communication with the drug reservoir 130 andpermits an operator of the pump 100 (e.g., a physician) to refill thedrug reservoir 130 in situ (e.g., while the pump 100 is implanted withinthe patient's eye 210). In general, the drug reservoir 130 can berefilled by inserting a refill needle into and through the refill port220. An additional drug refill port may, in certain exemplaryembodiments, be placed in fluid communication with the bottom chamber140.

Referring still to FIGS. 4A and 4B, pumping action, including theclosed-loop control process, may be controlled by the control circuitry170. In one embodiment, an induction coil 260 permits wireless (e.g.,radio-frequency (RF)) communication with an external controller (e.g., aportable control handset), which may also be used, for example, tocharge the battery of the control circuitry 170. The external controllermay be used to send wireless signals to the control circuitry 170 inorder to program, reprogram, operate, calibrate, or otherwise configurethe operation of the pump 100. The control circuitry 170 may, forexample, communicate electrically with the electrolysis electrodes 240in the bottom electrolysis chamber 140 by means of metal interconnects280 spanning the bottom wall of the electrolysis chamber 140. In oneembodiment, the electrolysis electrodes 240 are platinum. Alternatively,any other appropriate conductive material (e.g., copper, gold, or silveron parylene, ceramic, or a biocompatible insulator) may be used.Additional catalyst elements 290 (e.g., constructed from platinum) maybe located within the bottom electrolysis chamber 140 to act as arecombination catalyst to encourage the phase change of the electrolytefrom its gaseous state to its liquid state when the electrolysiselectrodes 240 are turned off. The electrolyte fluid contained withinthe bottom electrolysis chamber 140 may be a saline (i.e., NaCl and H₂O)solution, a solution that contains either magnesium sulfate or sodiumsulfate, or may be pure water or any non-toxic solution. Duringrecombination, some gases may diffuse out of the first chamber.

In one embodiment, a plurality of suture holes 295 are incorporated intothe outer shell 160 of the pump 100 to provide a means of quickly andstably attaching the pump 100 to a body portion at a treatment site. Thesuture holes 295 may include loops of material, such as, but not limitedto, parylene, that extend from one or more portions of the shell 160 andprovide anchoring locations at which a surgeon can suture the pump 100at a treatment site to stably secure the pump 100 in place. In oneembodiment, a glue and/or other affixation method may be used inaddition to, or instead of, a suture/suture hole 295 affixationarrangement to hold the pump 100 in place at the treatment site.

A plan view of an exemplary pump 100 having a cannula 120, suture holes295, and a check-valve coupler 300 for affixing a check-valve, is shownin FIG. 5. The coupler 300 facilitates affixation of the cannula 120 toa separate check-valve assembly by mechanical and/or adhesive means. Theillustrated pump 100 includes six suture holes 295 positioned at anouter edge of the shell 160 and along the length of the cannula 120 tofacilitate affixation of the pump 100 at a treatment site. The sutureholes 295 may have an inner diameter, for example, of 400 μm and anouter diameter of 800 μm, although larger or smaller suture holes may beused. Additionally, a greater or lesser number of suture holes 295 maybe used, and the suture holes 295 may be located at any appropriatelocation on the shell 160 and/or cannula 120 of the pump 100.

In an exemplary embodiment, the parylene layers used to form thediaphragm 150 and/or other pump layers have a 20 μm thickness. Asillustrated in FIG. 5, the outer dimensions of the drug chamber 130 mayform a substantially elliptical shape having dimensions of 9 mm×6 mm,while the outer dimensions of the corrugated diaphragm 150 may form anelliptical shape having dimensions of 7 mm×6 mm. The delivery cannula120 may be 6 mm long and 400 μm wide, with an inner channel dimension of20 μm×100 μm. In alternative embodiments, larger or smaller pumps and/orcomponents thereof may be used, and the pump 100 may have anyappropriate geometrical shape including, but not limited to, an ellipse,a circle, a square, or a rectangle.

A perspective view of an exemplary implantable pump 310 is shown in FIG.6, while an exploded perspective view of the pump 310 is shown in FIG.7. In this embodiment, the pump 310 includes a top layer 320 including adomed portion 330 with a cannula 120 attached thereto. A middledeflection layer 340 forms the diaphragm 150 dividing the drug chamberfrom the electrolysis chamber. As discussed above, this diaphragm 150may include corrugations 350 to facilitate expansion and contraction ofthe diaphragm 150 in response to electrolysis of gas from theelectrolytic fluid in the electrolysis chamber. In an alternativeembodiment, the diaphragm 150 may have a bellows type structure inaddition to, or in place of, the corrugations 350. The layers formingthe pump 310 may include, or consist essentially of, parylene.

The pump 310 further includes a bottom layer 360 with electrolysiselectrodes 380 coupled thereto or embedded therein. The electrolysiselectrodes 380 are coupled to integrated control circuitry 370 forproviding power to the electrolysis electrodes 380, and therebycontrolling the pumping of fluid from the drug chamber. The circuitry370 may be located in the same plane as the electrolysis electrodes 380or may be positioned below the electrolysis electrodes 380. The threeParylene layers 320, 340, and 360 may be bonded together using thermalbonding, or through other appropriate bonding techniques including, butnot limited to, chemical bonding, epoxy bonding, and/or pressurebonding. A drug chamber is formed between the top layer 320 and themiddle deflection layer 340, while the electrolysis chamber is formedbetween the middle deflection layer 340 and the bottom layer 360.

One or more openings (not shown) may be left for filling electrolyte anddrug separately into the electrolysis chamber and the drug chamber. Theopening may then bonded and the chambers sealed, e.g., by thermalbonding. Alternatively, as described above, one or more refill portsthat utilize a one-way valve can be incorporated to allow forfilling/refilling, flushing, etc. of the drug and/or electrolysischambers.

A pump 100, 310 may, if desired, include multiple cannulas 120 arrangedto extend from one or more locations on the pump 100, 310 towardmultiple treatment sites surrounding the pump 100, 310. In oneembodiment, each cannula has a separate check valve 220, pressuresensor, chemical sensor, and/or flow sensor 205 associated therewith. Inan alternative embodiment, a check valve 200 may be used to control theflow through multiple cannulas 120, and/or a single pressure sensorand/or flow sensor 205 may monitor conditions within multiple cannulas120. For example, the cannulas 120 may surround the dorsal nerve root ofa recently fused spine, with the pump 100, 310 impelling steroids for anextended period (e.g., six months) after surgery to reduce inflammation,improve healing time, and lower pain (and possibly the need for anothersurgery). Furthermore, the device can be superficially placed just belowthe fat pad, allowing a minimally invasive procedure to be performed toexplant the device with limited risk and cost to the patient (comparedto the cost/risk of removing a larger drug-delivery device or longcatheter). In an alternative embodiment, no cannula is required, withthe drug being pumped through one or more holes/perforations in one ormore walls of the drug chamber 130 directly into the surrounding body.

One embodiment of the invention includes a pump 100 including multipledrug chambers 130 each of which can be associated with separateelectrolysis chambers 140 or be driven be a single electrolysis chamber140. Separate cannulas 120 and/or refill ports 220 may be associatedwith each of the plurality of drug chambers 130. One embodiment of theinvention may include a plurality of electrolysis chambers 140, withseparate electrolysis electrodes 240 associated therewith. Refill ports220 may be placed in fluid communication with one or more of thechambers 130, 140.

In one embodiment, the diaphragm 150 is controllably expanded toward adrug chamber 130 using other methods in addition to, or in place of,inducing gas electrolysis from a fluid held within an electrolysischamber. Such methods may include, but are not limited to, mechanicallydriven means (e.g., threaded motors), electro-magnetically driven means,pneumatic means, or combinations thereof.

With reference now to FIG. 8, one embodiment of the invention includesan implantable drug-delivery pump 100 having a drug chamber 130 and anelectrolysis chamber 140 with a perforated shell 400 positioned abovethe drug chamber 130. The perforated shell 400 provides protection forthe pump components while allowing a body fluid to flow through theperforated shell 400 to offset any vacuum pressure generated on thesurface of the drug chamber 130 as the volume of drug within the drugchamber 130 is reduced through the pumping of the drug through thecannula 120 and into a treatment site.

More specifically, as drug is pumped from the drug reservoir 130 andless fluid is left therein, vacuum pressure is generally generated onthe outer wall 110 of the drug chamber 130. This pressure resists fluidoutflow from the drug chamber 130, thereby increasing the force thatmust be exerted by the expanding membrane 150 to expel fluid from thedrug chamber 130. In addition, because of the reduced drug volume heldwithin the drug chamber 130 after dosing, and the closed check valve 200in the cannula 120 preventing fluid from returning up the cannula 120towards the drug chamber 130, vacuum pressure may also be generatedagainst the drug chamber 130 as the diaphragm 150 of the electrolysischamber 140 returns to its original position. By providing theprotective shell 400 having one or more perforations 410 to permitingress of surrounding body fluid into the space between the shell 400and the outer wall 110 of the drug chamber 130, the vacuum pressureexerted on the drug chamber 130 is automatically balanced by theinflowing bodily fluid, thereby maintaining a consistent actuation timeand conserving battery power.

The protective shell 400 may be a substantially solid shell, while theperforations 410 may be of any size, shape, and/or number necessary toprovide a sufficient flow rate from the surrounding bodily fluid intothe cavity between the shell 400 and the drug chamber 130. Theperforations 410 may cover the entire portion of the shell 400 coveringthe drug chamber 130, or only a portion thereof.

The shell 400 may include, or consist essentially of, polypropylene.Alternatively, the shell 400 may include, or consist essentially of, anyother appropriate material such as, but not limited to, a biocompatibleplastic material, a metal (e.g., titanium, niobium, tantalum), or othermaterial providing sufficient rigidity and mechanical strength toprotect the pump 100 while exhibiting sufficient biocompatibility to beplaced within a patient for an extended period. In one embodiment, theshell 400, or a portion thereof, has a thickness greater than 0.1 mm.The perforated shell 400 may be at least partially coated by a coatingsuch as, but not limited to, a biocompatible material (e.g. parylene).

The perforated shell 400 has three main functions: mechanicalprotection, balancing vacuum pressure in the drug chamber 130, andintegration of the refill port 220. In particular, the hard shell 400provides protection against mechanical damage during implantation,refilling, or at any time that the pump 100 is exposed to largepressures (which, if transmitted to the drug chamber 130, may causeunwanted delivery of the drug). The mechanical strength of the shell 400can be designed and optimized by selecting different materials, shellthicknesses, 3-D profile, and geometry (e.g., shape, size, etc.) anddistribution of the perforations 410.

The perforations 410 may be large enough to create minimal resistance tofluid inflow and outflow, but small enough to provide adequateprotection against mechanical damage. For example, in some embodiments,the perforations 410 have diameters smaller than the diameter of arefill needle, thereby preventing its entry. In other embodiments, theperforations 410 are larger but covered, so that a uniformly solidexterior is presented to external objects that approach the pump 100.For example, each perforation 410 may have an overlying cover, which islarger in diameter than the perforation 410 and supported thereover bypillars or other appropriate structures. Alternatively, the cover may besupported over a perforation 410 by a mesh or screen. In one embodiment,the shell 400 comprises a meshed and/or woven structure.

With reference now to FIG. 9, one embodiment of the invention includesan implantable drug-delivery system including a pump 450 driven by apassive osmosis-based mechanism. Implantable drug-delivery systems thatutilize a passive mechanism for drug delivery can eliminate or limit theneed for control electronics and power sources, thereby potentiallyreducing size, cost, complexity, safety, biocompatibility concerns, etc.Such pump-delivery systems can be placed in proximity to the surgicalsite after a surgical procedure, enabling targeted dispensing of a drugthrough one or more cannulas 120 in a localized region. In particular,active or passive osmotic pumps can be beneficial to ocular applicationsby lowering the size, cost, and power requirements over existing pumps,while still delivering active medication directly to the anterior orposterior chamber or subretinal area.

In addition, some traditional drug-pump cannulas may be subject tobiofouling, or the clogging of tissue and cells in the cannula, whichprevents the outflow of drug—particularly in devices where considerabletime elapses between bolus injections. For example, if a drug pump onlyimpels drug every 24 hours, it is almost always dormant, and thereforedebris and cells can clog the system, making it less efficient orplugging the outflow. By providing an osmotic pump with continuousoutflow of drug, biological debris can be prevented from collecting dueto the continuous operation of the device.

In one embodiment, the osmosis-driven pump 450 includes activeelectronics, powered by a battery or inductive telemetry, to control theopening and closing of an active check valve 200, thereby achievingactive control of the pulsatile delivery of the osmotic device, whilestill keeping overall system power requirements below those of, forexample, electrolysis-based pumps.

In the exemplary embodiment shown in FIG. 9, the osmotic drug-deliverypump 450 includes a drug chamber/reservoir 130 containing one or moredrugs or other therapeutic delivery agents. A cannula 120, or other tubeor orifice, is in fluid communication with the drug chamber 130 tofacilitate accurate delivery of a drug held within the drug chamber 130to a targeted treatment site within a patient. The pump 450 furtherincludes an osmosis chamber 460 containing a solvent (e.g., water) andsolute (e.g., NaCl). A membrane 150 (e.g., a corrugated, elastic, and/orbellows membrane) separates the osmosis chamber 460 from the drugchamber 130.

At least a portion of an outer wall of the osmosis chamber 460 includesa permeable or semi-permeable membrane 470 that, for example, permitspassage of the solvent but is not (or is minimally) permeable to thesolute contained in the osmosis chamber 460. In one embodiment, thepermeable membrane 470 is manufactured as part of the osmosis chamber460. In an alternative embodiment, the permeable membrane 470 ismanufactured separately and integrated with the chamber 460 in aseparate step.

In operation, placing the pump 450 in a solvent (e.g., implanting thepump 450 in the body, the solvent consisting of biological fluidssurrounding the pump 450) results in a net flux of the solvent acrossthe permeable or semi-permeable membrane 470. The magnitude of the fluxis determined in part by the degree of permeability of the membrane 470to the solvent. This net flux results in a flow of solvent (e.g. water)into the osmosis chamber 460 from the surrounding body, which in turnincreases the pressure in the osmosis chamber 460. The increase inpressure deflects the membrane 150 into the drug chamber 130, therebydecreasing its volume and forcing the drug held within the drug chamber130 through the cannula 120 and out to the targeted treatment site.

In one embodiment, the pump 450 includes other (e.g., biocompatible)components, such as a protective shell, housing, enclosure, or covering,that provide protection to, and/or help maintain the structuralintegrity of, the pump 450. Other components that may be incorporatedinto the pump 450 include refill ports for one or both of the chambers130, 460, one or more flow and/or pressure sensors 205, and/or one ormore check-valves 200 to prevent back-flow. The pump 450 may alsoincorporate active electronics, e.g., to monitor flow rate of the drug,record dosing schedules, and/or ensure proper function.

As described further below, the osmotic drug-delivery pump 450 may bemonolithically microfabricated utilizing multiple polymer layers thatare later bonded together using any of a number of common packagingtechniques (e.g., thermal bonding of the layers). In one embodiment, thepump 450 utilizes parylene or other biocompatible material to achieve anactive device with full biocompatibility. For example, the drug chamber130, cannula 120, and check valve 200 may all be formed from one or moreparylene sheets. In one embodiment, the pump 450 is flexible and easy tofit into a protective shell with optimized implantation 3D geometry.

With reference now to FIGS. 10-12, another embodiment of the inventionincludes an implantable drug-delivery system including a pump 500 havingan osmosis chamber 510 to prevent, as earlier described, theaccumulation of vacuum pressure on the drug chamber 130. This osmosischamber 510 may be utilized to automatically balance a vacuum pressureon the drug chamber 130 after each electrolysis dosing, therebymaintaining a consistent actuation time and conserving battery power. Asalso illustrated in FIGS. 10-12, the pump 500 includes an electrolysischamber 140 and electrolysis electrodes 240, as described hereinabove.

The osmosis chamber 510 overlies the drug chamber 130 and these twochambers are separated by a fluid barrier such as, but not limited to, acorrugated diaphragm 520. The top layer 530 of the osmosis chamber 510may include a thin-film, semi-permeable osmotic membrane 540 that may,in one embodiment, be integrated with (e.g., uniformly attached to) aperforated protective hard shell 550. The perforations expose theosmotic membrane 540 to surrounding fluid. In an alternative embodiment,no permeable hard shell 550 is required, with the semi-permeable osmoticmembrane 540 itself being structured with sufficient strength andrigidity to provide a protective covering for the pump 500. In oneembodiment, one or more of the chambers 130, 140, 510 include a refillport in fluid communication therewith. For example, a refill port 560may be coupled to the osmosis chamber 510, and may, for example, bemounted through the hard shell 550. The osmosis chamber 510 may be filedwith a fluid such as, but not limited to, a solute and solvent (e.g.,NaCl in water). Fluids that may be used in the osmosis chamber 510 alsoinclude a saline solution, a solution including magnesium sulfate, asolution including sodium sulfate, pure water, or any non-toxicsolution.

Again, in operation, when current is supplied to the electrolysiselectrodes 240, the electrolyte generates electrolysis gas, expandingthe diaphragm 150, and forcing liquid out of the drug chamber 130through the cannula 120. When the current to the electrolysis electrodes240 is stopped, and the gas dissipates back into its liquid state withinthe electrolysis chamber 140, the corrugated diaphragm 150 above theelectrolysis chamber 140 recovers its space-efficient corrugations.Because of the reduced drug volume after dosing and the closed checkvalve 200 in the cannula 120, vacuum pressure is generated against thedrug chamber 130 as the diaphragm 150 above the electrolysis chamber 140returns to its original position.

To counteract this vacuum pressure, fluid (e.g., water) from surroundingbodily fluids flow through the permeable membrane 540 and into theosmosis chamber 510. More specifically, the osmosis chamber 510 mayinitially be charged with a liquid that is hypertonic relative to theexternal bodily fluid. As a result, water tends to flow through theosmotic membrane 540 and into the osmotic chamber 510. The incomingwater equalizes the pressure on both sides of the upper drug chambermembrane 520, with the equalized pressure in the drug chamber 130helping to reduce the deflection of the diaphragm 150 necessary togenerate a check valve cracking pressure, therefore saving pumpoperation power.

In one embodiment, when the pump 100 is in rest status, osmotic pressurewill reach balance with the drug chamber 130 pressure, which is lowerthan a check valve cracking pressure, until the next dosing whichcreates lower pressure in the drug chamber 130, after which a newbalance status will be reached. The concentration of the osmosis chamberis selected such that the balance pressure after the final dosage won'texceed a check valve cracking pressure.

The osmotic pressure driving the flow depends on the soluteconcentration in the osmotic chamber 510 (relative to the surroundingfluid) and the degree of permeability of the membrane 540. In oneembodiment, the solute concentration in the osmotic chamber 510 is lowenough to keep the osmotic pressure well below the cracking pressure ofthe cannula check valve 200 (so that fluid is never improperly expelledfrom the drug chamber 130).

As water fills the osmosis chamber 540, in effect replacing the volumeof drug pumped out of the drug chamber 130 after each dosage, theconcentration of osmotic solute decreases. Accordingly, while theinitial solute concentration cannot be so high as to cause fluid to bedriven out of the drug chamber 130, it should be sufficiently high that,despite its gradual dilution, it remains adequate to draw liquid throughthe osmotic membrane 540 until the supply of drug has been fullydispensed. At that point, the drug chamber 130 may be refilled throughthe refill port 220, and the osmosis chamber 510 is purged and refilledwith the hypertonic liquid through the osmosis chamber refill port 560.In one embodiment, filling the drug chamber 130 with the osmosis-chamberrefill port 560 open may accomplish the necessary purging of the osmosischamber 510.

In another embodiment, the invention includes an outer package toprovide a protective enclosure for at least a portion of the pump.Exemplary packages 600 are shown in FIGS. 13 through 19. The package 600may be manufactured, at least in part, from materials such as, but notlimited to, a metal (e.g. titanium, tantalum, or niobium), an alloy(e.g. nitinol (TiNi)) polypropylene, polyimide, polyetheretherketone(PEEK), glass, ceramic, and/or epoxy. Depending on the material used andthe shape desired, the shell may be fabricated using techniques such as,but not limited to, computer numerical control (CNC) milling, stamping,extrusion, and/or injection molding. The package 600 may be at leastpartially coated by a coating such as, but not limited to, abiocompatible material (e.g. parylene).

A first exemplary package 600 for an implantable drug-delivery pump isshown in FIGS. 13 and 14. In this embodiment, the package 600 includes ahermetic enclosure 635 and a dome-shaped protective shell 160 that has arecessed shape (including a concave lower portion 610) that may beobtained through, for example, hydraulic stamping or CNC-machining. Thedimensions and height of the device depend on the function, location,size of electronics and power source, etc., and can be tailored to aspecific application and/or patient. In one embodiment, the package 600is designed for intra-ocular deployment and has dimensions ofapproximately 14 mm (L)×10 mm (W)×4 mm (H). In alternative embodiments,smaller, larger, or differently proportioned shells may be utilized. Thehermetic enclosure 635 may provide a housing containing elementsincluding, but not limited to, the control electronics, a power source,and/or a communication means, as described herein. Elements such as theelectronics and power source may be disposed within the hermeticenclosure 635 in a stacked configuration to provide a smaller footprint,or side-by-side to provide a shallower form factor.

In one embodiment, the hermetic enclosure 635 includes an endplate 620enclosing the recessed area, which can be attached thereto in a mannersuited to the material, e.g., welding or bonding, to provide a hermeticseal. The hermetic enclosure 635 (or another surface of the enclosure)may include feed-through elements to allow electrical connections tospan the internal electronics and external elements accessible outsidethe hermetically sealed pump. These external elements may include, forexample, a coil for a wireless charging/telemetry link, the electrolysiselectrodes and sensor connections in the pump, and/or the electrodes ina stimulation device, etc. Removal of the endplate 620 facilitatesaccess to these “external” components. The coil may be molded to thepackage 600. Alternatively, the hermetic enclosure 635 may be fabricatedfrom injection-molded plastic or potted epoxy, such that all of theelectronics and power source are hermetically encased within thehermetic enclosure 635 as it is manufactured so that no separateendplate is necessary. For example, in one embodiment the hermeticenclosure 635 includes an upper an lower surface that are hermeticallysealed together after placing the circuitry 170 and/or other componentstherein.

One or more cannulas 120 may extend through the shell and be in fluidcommunication with one or more drug chambers housed within the package600. The cannula(s) 120 may be of any appropriate length, diameter, andcurvature as required to deliver drug to a particular treatment site. Inone embodiment, a silicone or similar tube is added around the cannula120 (and may be backfilled with a silicone-type adhesive) for addedstrength/durability and/or to create rounded edges to minimizeirritation to surrounding tissue and at the incision/point of entry(e.g., into the vitreous cavity).

The shape and size of the package 600 are dictated by its function andcan be designed to suit any particular geometry. For example, in oneembodiment, the package 600 houses an intra-ocular drug pump and isshaped to match the curvature of an eyeball upon which it is to besurgically mounted. This may be achieved by milling, injection molding(in the case of polymers such as polypropylene), or by doming thestructure, e.g., with a hydraulic press and tooling (in the case of ametal such as titanium). The endplate 620 can be shaped to match thecurvature of the package 600 so that the interior volume of the package600 remains constant. In another embodiment, the thickness and/or widthof the package 600 are tapered, providing a teardrop shape. The profileand edges of the package 600 may be rounded to minimize the risk ofdamage to tissue structures in direct contact therewith, as well as tomaximize comfort for the patient and ease implantation for the surgeon.For example, the rounded corners and edges (alone or in conjunction withthe teardrop shape previously mentioned) on an intraocular drug pump canease surgical implantation when inserted into an incision in theconjunctiva or sclera of the eye, or the parenchyma of the brain, andalso reduce irritation or inflammation at the site of implantation.

In one embodiment, the device is a small drug pump with a protectiveshell 160 that covers a drug reservoir and an electrolysis chamber. Theshell 160 may be made from a durable material such as, but not limitedto, titanium, nitinol, tantalum, niobium, polypropylene, polyimide,glass, ceramic, PEEK, and/or epoxy, as described above, and may be addedto protect components of the pump, such as, but not limited to one ormore drug chambers. The shell 160 may have perforations or holes topermit the influx of a fluid for pressure equalization of the drugchamber of the pump.

A shell 160 (with a drug chamber 130 and electrolysis chamber 140enclosed thereunder) may be coupled to, and sit atop, the hermeticenclosure 635, enclosing the electronics and battery. The drug chamber130, electrolysis chamber, and/or protective shell 160 may be attachedin a manner suitable to the material of the hermetic enclosure 635, suchas, but not limited to, adhesive means. In an alternative embodiment,the shell 160, and pump elements (e.g. drug chamber 130 and electrolysischamber), may be located adjacent to the hermetic enclosure 635 asopposed to atop the hermetic enclosure 635, thereby reducing the overallheight. An example package 600 having a shell 160 (with drug chamber 130and electrolysis chamber 140 enclosed thereunder) adjacent to theelectronics and power source sub-assemblies 660 is shown in FIGS. 20 to23. Affixation using an adhesive has the advantage, for example, ofallowing a two-step sterilization process. For example, it may not bepossible to expose the package 600 to gamma radiation (e.g., because itencloses vulnerable electronics or is itself subject to damage), but itcan be sterilized with, e.g., ethylene oxide gas. The shell 160 and pumpelements, however, may be impervious to ethylene oxide gas but amenableto sterilization with gamma radiation. In such implementations, it ispossible to sterilize the shell 160 and pump elements with gammaradiation, attach it to the hermetic enclosure 635 in a sterileenvironment, and then sterilize the whole package 600 using ethyleneoxide.

In one embodiment, the cannula 120 is fed through the shell 160 and theinterface between the cannula 120 and the shell 160 sealed with asilicone or other suitable material, e.g., epoxy. This configuration maybe beneficial in providing protection to the pump structure withoutrequiring an additional shell above the dome of the pump to addstructural support. Similarly, the shell 160 may be encased with theother sub-assemblies in an injection-molded or potted epoxy enclosure.The cannula 120 may be contained within a tubing sleeve made, forexample, from silicone or a similar material, to provide additionalstructural integrity and protection to the cannula 120. This sleeve maybe backfilled with a silicone or similar adhesive.

In the case of a refillable drug pump, in which the drug reservoir isrefilled via a needle, the rigid enclosure can also serve as a safety“stop” to prevent the needle from going too far and damaging the deviceor injuring the patient and/or to assist in guiding the needle into therefill port. As shown in FIGS. 18 and 19, the outer shell may contain arefill port 690 fabricated from silicone or a similar material. Therefill port 690 may be located at any appropriate position on thepackage 600 and provide easy access by a surgeon after implantation,using the rigid shell to prevent over-insertion of the needle oralternately to guide the needle (e.g., a channel in the rigid shell).

As shown in FIGS. 15-19, the shell may include eyelets 670, or otherstructures extending from the hermetic enclosure 635, for securing thedevice to a treatment site using sutures. In one embodiment, the eyelets670 are rounded to prevent irritation or damage to the surroundingtissue, and are located at the top of the device to aid in implantingand securing the device against the eye. This can also be helpful in thebrain, spine and knee. In an alternative embodiment, one or more sutureeyelets 670 may be positioned at any location around an exterior of apackage 600 to allow the device to be secured in place easily by thesurgeon. As described above, in one embodiment, the package 600 mayinclude a portion including one or more perforations to enables a fluidflow to pass through the shell to an interior portion thereof to providepressure equalization, solvent permeation in an osmotic pump, etc.

In one embodiment, as illustrated in FIGS. 18 and 19, the shell ismanufactured with one or more coils 680 integrated therein to providewireless telemetry and/or recharging. This may be achieved, for example,by injection molding of the package 600 with the coil 680 in place.

FIG. 24 depicts a schematic sectional view of another pump 100embodiment that has a package 600 including a hermetically enclosure 635containing the electronics and battery. Here a ceramic header 675 withelectrical feed-throughs 685 is brazed to top of the biocompatible metal(e.g. titanium, niobium, tantalum or nitinol) case to form the hermeticenclosure. However, the metal or ceramic alone can form the entirehermetic enclosure 635 with insulated feed-throughs 685 brazed on. Thefeed-throughs 685 are for the control of the electrolysis electrode, thesensors and/or for the connection to the telemetry coil/antenna (notshown) that is molded on the shell 160. The ceramic electrolysis chip665 containing the electrolysis electrodes is located on top of thehermetic enclosure 635. A spacer 670 with a set thickness may be placedaround and beneath the edge of the diaphragm 150 to create volume. Inone embodiment, there is an opening formed in the spacer 670 to create afill hole for the electrolysis chamber 140 that can be sealed afterfilling the electrolysis chamber 140 with an electrolyte. A filling tubecan be coupled to the fill hole and sealed after filling. The spacer 670may be formed from a material such as, but not limited to, a metal (e.g.Titanium), ceramic, plastic, and/or other biocompatible material. Thetop drug reservoir wall 160 may have two fluid ports. One port 655 is tocouple with a cannula for drug delivery and the other 220 for connectingwith a refill port through a tube (not shown).

A. Electronic Subsystems for Implantable Pumps

Power for the device can be provided by several different technologiesincluding both standard chemical-based batteries and/or capacitors thatstore a charge in an electric field. It is also possible to providepower via a wireless inductive link instead of on-board power-storagecapabilities. (Alternatively, as described below, the inductive link canbe used to charge/recharge an on-board battery or capacitor.) The powersource may include a coil in an inductive link, which may include aferrite core.

In some embodiments, the power source is provided by a primary (i.e.,non-rechargeable) or secondary (i.e., rechargeable) lithium-basedbattery (e.g., a lithium-ion, lithium-polymer, or lithium phosphorusoxynitride (LiPON) battery). In one embodiment, the device utilizes aLiPON thin-film solid-state battery, which offers high charge density inextremely thin and small form factors. In addition, the solid-statestructure of LiPON is inherently safer than many other lithium andliquid/chemical based batteries that can suffer outgassing, leakage, andeven explosion. Providing an extremely thin power source allows, forexample, for a flexible design that can fit the curvature of a shelldesigned for the eye, brain and spine. To increase storage capacity, itis possible to stack several layers of thin-film batteries within ashell.

Due to safety concerns, rechargeable lithium and other batteries,especially those used in implantable medical devices, are typicallyenclosed in a metal case for protection and biocompatibility. In oneembodiment, an a rigid outer enclosure or shell (formed, for example,from a biocompatible material such as, but not limited to, titanium,tantalum, nitinol, or niobium) may encase components of the pump toprovide protection for the components. As the protective shell may houseboth pump components and electronic components such as, but not limitedto the battery, the device electronics and the battery technology may beenclosed in a single, hermetically-sealed shell without the need toprovide separate shells for different components. In one embodiment, thebattery and electronics power and control a drug pump made fromparylene. In a related embodiment, a LiPON battery is deposited on alayer or sheet of parylene that may or may not be integrated with theparylene pump structure.

An energy-storage source suitable for use in connection with a drug pumpmay include a battery and/or capacitor integrated into the implantabledevice. In one embodiment, the battery utilizes a LiPON thin film as alithium electrolyte. LiPON may be advantageous, for example, byproviding improved size/geometry, safety, and/or charge capacity thancertain other technologies. Using LiPON technology, for example, it ispossible to achieve a high charge density in a small form factor, whichmay be critical for implantable devices. LiPON batteries can also bemade extremely thin, allowing for a flexible design that can fit thecurvature of an implantable device designed to lie flat against the eyeor brain, for example. Because they are inherently thin, severalindividual cells may be stacked to increase voltage (by connecting thecells in series) or to increase capacity (by connecting them inparallel) while still maintaining a thin profile.

LiPON batteries may be manufactured by depositing thin layers ofdifferent materials on a substrate to form the anode, cathode, andelectrolyte. After deposition, the layers are typically sealed (e.g., bymeans of a laminate) in order to prevent chemical reactions caused byinteraction with the surrounding air that would significantly shortenthe life of the battery. The battery's lifespan can further be extendedby installing the battery in a hermetically sealed enclosure containingan inert environment (e.g., argon). In one embodiment of an implantabledrug pump, the substrate comprises, or consists essentially of, apolyimide sheet (e.g., KAPTON). The advantage of depositing the batteryonto a polyimide sheet is that this substrate can additionally serve asthe circuit board for the electronics, providing electricalinterconnects between different components that are mounted on thepolyimide substrate through standard electronics-manufacturingtechniques (solder, conductive epoxy, etc.). Therefore, the battery andelectronics are all borne by a single monolithic substrate. For example,the underside of a polyimide sheet can support multiple battery layerswhile the electronic components and integrated circuits can be mountedon the topside.

In a related example, the battery layers are deposited on a thin sheetof parylene, from which the mechanical pumping mechanism may be formed.This approach also has the benefit of providing a single, integratedstructure for the battery and another component of the implant (in thiscase, the pumping mechanism). In alternative embodiments, the batterylayers can be deposited on a sheet of parylene that is not used for anyother function. Parylene can also be deposited over the exposed batterystructures (e.g., anode, electrolyte, cathode) in sufficient thicknesses(e.g., 3 μm or greater) to ensure pinhole-free seals protecting thebattery structures from exposure to surrounding air.

In medical devices it is often desirable to include a backup powersource, such as a second battery, in the event that the first batteryfails. The second battery can serve as a total replacement for the first(so that it continues to power all functions) or it can exist merely toprovide enough power to properly shut the device down, alert the user,or perform some other critical function in the event of a failure of themain power source. LiPON batteries, for example, are well suited to thistask, at least because of their stackable nature. In one embodiment, thebattery is actually two (or more) battery elements stacked on top ofeach other. The capacity of the backup battery can match that of themain battery, or it can store only a fraction of the energy stored inthe main battery (e.g., 20% of the main battery's capacity). Circuitryincorporated in the electronics sub-assembly of the implantable device,or even within the battery sub-assembly itself, can detect failure (suchas a short circuit or depleted power) and switch to the backup batteryif necessary.

One embodiment of the invention may include a power supply including arechargeable battery, such as, but not limited to, a rechargeable LiPONbattery. This may be highly desirable in an implanted device, as itobviates or at least defers the need for additional surgical proceduresfor changing batteries, etc. In one embodiment, recharging isaccomplished through utilization of an RF-coupled wireless power linkand, for example, a near-field (e.g., inductively coupled) link,typically employing coils in the transmitter and receiver, or afar-field link, which may employ antennas in the receiver and coil. Thefrequency of operation can be chosen to suit the application; higherfrequencies (e.g., 10 MHz) typically facilitate use of smallerelectronic components, as well as enabling greater tissue penetrationand higher efficiencies in power coupling, while lower frequencies(e.g., 400 kHz) typically offer lower power consumption and lesspotential tissue heating due to absorption.

In one embodiment, the substrate on which the battery is deposited alsoincludes recharging circuitry such as, but not limited to, a coil and acapacitor connected to form a resonant circuit for inductive coupling, arectification stage that converts the resulting alternating current (AC)to direct current (DC) and filters the resulting DC (e.g., through alow-pass filter stage) and a voltage-regulation stage that maintains theproper charging voltage regardless of external influences (movement ofthe coil, etc.) during the charging process. These components may bediscrete or can be fabricated using well-known semiconductor techniquesduring the same overall manufacturing process that creates the batterylayers.

In another embodiment, recharging capability is accomplished using aphotovoltaic cell on the same substrate as the LiPON battery. Forimplants that are close to the surface of the skin, (e.g., anintraocular application whereby the pump is surgically implanted justbelow the conjunctiva of the eye, an intracranial application wherebythe pump is surgically implanted just below the skull, or aneurosurgical application whereby the pump is implanted along the nerveroot), energy can be coupled to the device via the photovoltaic cell anda light source, e.g., a laser focused on the location of the implant.

Suitable electronics may provide control and monitoring capabilities aswell as any additional required functions for the device. In oneexemplary embodiment, the electronics control the pumping mechanism andmeasure the amount of drug administered. The complexity of theelectronics depends on the required functionality, but may includehighly complex and integrated functionality that can be packaged insmall forms. In one embodiment, the electronics includes off-the-shelfcomponents such as, but not limited to, microcontrollers, op-amps,transistors, resistors, and/or capacitors enclosed in small packages.These components may be mounted on a printed circuit board that provideselectrical interconnectivity. In one embodiment, this printed circuitboard is of the flex circuit variety (on a polyimide, e.g., KAPTONsubstrate) to minimize thickness and also provide flexibility so theelectronics can match the curvature of the shell (which is itselfdesigned to match the curvature of the eye, knee or brain).

In one embodiment, to minimize size and dimension, the components arepackaged together in a system-on-chip (SoC) configuration, e.g., usingchip-scale packaging or wafer/die-level and wirebond assembly. Inanother embodiment, the electronics functions may be custom-designed inan application-specific integrated circuit (ASIC).

The electronics may be coated with a thin conformal coating (such as,but not limited to, epoxy or parylene) to prevent the possibility of ashort circuit in the case of a conductive outer shell. Alternatively,the inside of the conductive shell may be coated to prevent shorting.The electronics may also be potted in epoxy either with the shell, orthe epoxy potting may serve as the shell itself. The electronics may behoused (e.g., in die or wafer form) in a parylene structure forming aportion of the pump system. The electronics may be wirebonded together,or connective traces may be integrated into the parylene.

In one embodiment, implantable pumps may include means of communicatingwith, and/or charging, the pump after implantation into a body. This maybe advantageous, for example, where hardwired connections to a supplypower and/or data communication functionality is impractical for animplanted device. As a result, embodiments of the present invention mayutilize a wireless telemetry configuration, whereby power and data aretransferred to and from the implant using electromagnetic radiationthrough means including, but not limited to, an RF link. In suchembodiments, the microelectronic implantable device may be coupled to anexternal device (a “reader/charger”). This external device may providefunctions such as, but not limited to, a power supply, batteryrecharging, and/or forward and reverse telemetry. For example, fordevices that do not incorporate internal energy-storage capabilities(i.e., battery or capacitor), the external device can be used to providepower when in proximity to the implanted device, while for devices thatincorporate an internal battery or other energy-storage device, theexternal device can be used to recharge the energy-storage device. Theexternal device can also be used to transmit data to the implanteddevice and/or receive data sent by the implanted device. This data mayinclude, but is not limited to, pump performance data, drug storageinformation, and/or medical readings. These functions may be integratedinto a single external device, or may be divided among multiple devices.For example, one device may provide power and recharging capabilitieswhile a different device may provide data telemetry functionality.

In one embodiment, the reader/charger (which may be a single device ormultiple devices) is controlled by a microcontroller, microprocessor,FPGA, or other digital logic device as well as ancillary circuitry(e.g., random access memory, power regulation, etc.) to enable programstorage and otherwise allow the processor to perform its function, and apower source such as rechargeable batteries or a transformer andregulator to facilitate connection to line voltage (110 VAC/220 VAC).The reader/charger may also incorporate non-volatile memory such asflash memory to store data of various types. The reader/charger may haveUSB or other interface capabilities to allow for data download, firmwareupdates, etc. In addition, the reader/charger may also incorporate auser interface, with a display (e.g., an LCD) that shows information,and buttons or a keypad enabling the user or clinician to interact withthe reader/charger (and, thereby, the implanted device). In addition,the reader/charger includes a coil or antenna and driver circuitryincluding a power-amplification stage (e.g., class-C or class-E)specifically designed to couple to resonant circuitry (i.e., a coil andcapacitor tuned to the resonant frequency) in the implantable device.The coil/antenna may be located within the same enclosure that housesthe other components, or it may be external to the enclosure, forexample, to facilitate charging and data transfer.

In one example, the implantable device is an intraocular drug pumpconfigured for surgical implantation below the conjunctiva on the eye orbrain. In this embodiment, the coil/antenna may be separate from therest of the reader/charger and installed in a pair of eyeglasses, an eyepatch for the eye, a headband for the brain, a kneebrace for the knee,or even a hat, and connected to the main reader/charger circuitry by acable (or, in some cases, wirelessly). Desirably, the coil isstrategically located in a wearable appliance such that, with theappliance properly and naturally positioned on a user, optimal alignmentbetween the implant coil and the reader/charger coil is enforced. Thismaximizes energy transfer and therefore minimizes recharge time. In aneyeglass configuration, for example, the frame, when worn, will have aconsistent alignment with the anatomy that does not vary substantiallyacross wearers. This configuration enables the patient to wear theeyeglasses comfortably during the recharging cycle (which, depending onmultiple factors, may take tens of minutes to a few hours). The bulk ofthe reader/charger can be located elsewhere, such as, but not limitedto, in a unit that may be clipped to a patient's belt.

In one embodiment, the implantable device can communicate with areader/charger including an audiovisual component, such as, but notlimited to, a pair of “video glasses” or virtual-reality goggles. Theeyeglasses may, if desired, have integrated LCD displays similar tovirtual-reality goggles or the “video glasses” currently being sold tointerface to audiovisual devices such as iPods. These glasses arecapable of displaying video images. The patient can comfortably watch amovie or television show, for example, or an informative or educationalvideo relevant to his or her treatment. The display can also be designedto display information regarding the charge/data telemetry cycle, suchas time elapsed/remaining, percent charged, etc.

In addition, the displays may be offset relative to the patient's lineof sight so that the patient is forced to view the display at an angle,for example by turning his or her eyes toward the left or the right.This can be useful in achieving optimal coupling to an implant on one ofthe patient's eyes (e.g., so that the coupling occurs through air, whichcauses lower attenuation of the signal power than coupling through theflesh and bone near the temple).

In one embodiment, implantable pump systems in accordance with theinvention may include a power and/or data telemetry system. For example,a power telemetry system can convert received AC signals transmitted bythe external device coil into a DC voltage, which can power the pumpand/or recharge the pump's internal power supply. Power transmission isunidirectional and may be accomplished by wirelessly coupling power froman external coil to an internal coil integrated with the pump devicepackaging. In one embodiment, the internal coil includes or consistsessentially of a single or multiple strands (e.g., Litz) of wire withpolymer insulation thermally formed by heat treatment into a specificshape. In particular, the coil can be shaped to conform to an anatomicalsurface, e.g., the eye, to which the pump is attached. In anotherembodiment, the coil is fabricated through the deposition and etching ofa conductive film (e.g., of gold or silver). In yet another embodiment,the coil is fabricated through a lithographic process. More generally,the coil may be fabricated according to any approach convenient to theoverall manufacturing process; numerous alternatives (e.g., using Litzwire) are well-known in the art. In an exemplary embodiment, animplantable gold coil, having a diameter of 1 cm, can achieve >100 mWcoupling power using a portable, wearable, external coil.

A data telemetry link may use the same set of coils as the powertelemetry link, or may use a separate coil. In addition, the implantedcoil can serve as both the transmit and the receive coil. The datatelemetry functionality can be used, for example, to program deviceparameters before or after implantation, verify proper programming andfunctionality, and download status alerts, dosing schedules, and otherrelevant information stored by the pump (e.g., in non-volatile memory).In various embodiments, antennas and/or coils may be located inside orintegrated within a shell material for a pump system (in the case ofnon-attenuating materials such as polypropylene) or on the outside (inthe case of metals and other shielding materials). Depending on thelocation of the device, it is also possible to locate the coil orantenna a distance from the device enclosure, e.g., a deeply implanteddevice with a coil located close to the skin surface. In one embodiment,a telemetry/recharging coil may be integrated into a parylene structureforming a portion of the pump system.

If the application does not require power telemetry or data telemetryafter implantation, an implantable pump in accordance with the inventioncan also incorporate a simple and inexpensive unidirectional, opticaldata-telemetry system (typically requiring fewer components, and lesscost and space, than a radio frequency or inductive telemetry link)utilizing, for example, a photodiode or phototransistor. In oneembodiment, an external device transmits light signals (for example viaa laser or LED) that have been modulated with data; these signals aredetected by the photodiode or phototransistor and interpreted by thepump-borne microcontroller or other control circuitry. In oneembodiment, the phototransistor and device electronics are located in anenclosure made from a material such as, but not limited to,polypropylene, that is transparent to the wavelength of the opticalsignals. In another embodiment, the electronics and phototransistor arelocated in an opaque (e.g., titanium) enclosure containing a transparent(e.g., sapphire) window hermetically sealed (e.g., through a brazing orwelding process). One benefit of this sapphire window is to allow an LEDlight source, attached to and controlled by the electronics, inside theenclosure to signal the patient or another use of some type of message,such as an error light or low battery signal. Other indicators inaddition to light include vibration, audible signals, or shock (such astranscutaneous neural stimulation).

A variety of modulation techniques and error detection/correctionmethods may be implemented. In an exemplary embodiment, the opticaltelemetry is used to program pump settings (e.g., the current date andtime, the desired flow rate, dosing schedule, etc.) immediately prior toimplantation, without removing the device from its package (assuming thepackaging material is penetrable by the wavelength of the particularlight source).

The optical communication can be made bidirectional (thereby enablingthe pump to transmit data as well) by adding a light-emitting diode(LED) to the pump circuitry. The LED can emit in the infrared or visiblespectrum; for example, an indicator LED may be used for communicationfunctions in addition to display. The bidirectional communicationenables the pump to communicate with an external device, for example, toverify proper programming and settings before implantation. The LED mayalso be used as a photodiode either in photovoltaic mode or photocurrentmode, thereby saving cost and space by using a single component for bothtransmit and receive functions.

In one embodiment, the control circuitry described herein may be used todetect electrical failures and, for example, switch to a backup battery,if necessary. More generally, the control circuit can be configured todetect any number of failure conditions and to take appropriateameliorative action. For example, if a malfunction or fault state in thepumping mechanism is detected, the control circuitry may trigger analert to the patient. The alert may take the form of an optical signal(from the LED described above, for example, which will be immediatelyvisible in ocular deployments); vibration; transcutaneous electricneurostimulation (e.g. giving an electrical shock to the eye); or anaudible signal. In one embodiment, the alert may include one or morelights blinking from an LED on the surface of the pump to alert patientin mirror, or LED on an undersurface of a pump to alert the patient'seye through endoillumination. Alerts may be used to notify a patient ofevents such as, but not limited to, malfunction, low battery, low drug.The control circuitry may communicate details of the failure conditionto the wireless reader when it is brought into proximity. Other alertssuch as audible signals (e.g. beeping), noises, vibration, andelectrical shock may also be used in addition to. Or instead of, anoptical signal, as described above.

B. Methods of Manufacture

In one embodiment of the invention, an implantable drug-delivery pump,or components thereof, may be manufactured using techniques including,but not limited to, bonding (e.g., thermal bonding), lithographicetching, and/or other suitable manufacturing techniques. Exemplarytechniques for manufacturing various components of the pumps describedherein are described below. It should be noted that the methods ofmanufacture described below are presented as representative examples,and any of the pumps and/or components thereof may be formed using anyof the manufacturing methods described, as appropriate, or othersuitable methods.

B.1 Method of Manufacturing Top Layer of Drug Chamber and Cannula

An exemplary method of manufacturing a drug chamber 130 with integratedcannula 120 for a pump 100 using lithographic fabrication processes isshown in FIGS. 25A-25F. In this embodiment, a pump 100 having a drugchamber 130, electrolysis chamber 140, and integrated cannula 120 isformed from a plurality of patterned parylene layers. The fabricationprocess flow includes the steps of:

(a) Spin-coating a thin photoresist layer (e.g., 1 μm) onto a siliconsubstrate as a sacrificial layer for releasing the finished device fromthe substrate.

(b) Depositing a first parylene layer (having a thickness, for example,of approximately 20 μm). This layer forms the top of the drug chamberand delivery cannula.

(c) Spin-coating a thick photoresist layer (having a thickness, forexample, of approximately 20 μm) as a sacrificial layer that defines theinterior dimensions of the drug chamber 130 and the cannula 120.Lithographic patterning by differential exposure may be used to createcorrugations in the photoresist surface (e.g., with a 10 μm pitch).

(d) Depositing a second parylene layer (having a thickness, for example,of approximately 20 μm), which forms the bottom and the side of the drugchambers and delivery cannula 120.

(e) Patterning the parylene layers in an RIE oxygen plasma using a thickphotoresist layer as a mask.

(f) Removing the sacrificial photoresist layers by subjection to aphotoresist stripper such as, but not limited to, acetone. This allowsthe device to be removed from the silicon substrate.

In one embodiment, by forming components of the pump 100 from aflexible, biocompatible material such as, but not limited to parylene,the drug chamber 130 and cannula 120 are both appropriate formimplantation within a body for safe extended use. Similarly, multipleparylene layers can be processed to make other layers of a pump 100,such as, but not limited to a bottom layer of an electrolysis chamber140.

In one embodiment, a pump 100 may be manufactured by separately formingthe discrete layers of the pump 100 (e.g., an upper surface of a drugchamber 130 with integrated cannula 120, a diaphragm 150 dividing thedrug chamber 130 and electrolysis chamber 140, and/or a bottom later ofan electrolysis chamber 140), and thereafter bonding these layerstogether through, e.g., thermal and/or chemical bonding.

A top layer 700 of a drug chamber 130 including an integrated cannula120 (as shown in FIG. 26) may be manufactured through methods including,but not limited to, molding and/or lithographic etching techniques. Anexemplary method of forming a top layer 700 is described below. The toplayer 700 may have dimensions such as, but not limited to, 9 mm indiameter and 4 mm in height, with a 9 mm cannula 120 with amicro-channel (9 mm in length, 150 μm in width and 20 μm in height).

In one embodiment, the top layer 700 is formed by coating a layer ofmaterial, such as, but not limited to, parylene, of a predeterminedthickness onto a mold (e.g., a metal mold formed, for example, fromaluminum). After the parylene coating has set, the resulting parylenedome structure may simply be peeled off of the mechanical mold. Acannula 120 may thereafter be inserted into, and/or bonded onto, theparylene structure through a preformed hole. The preformed hole in thetop layer 700 may be formed after molding the top layer, for example bypiercing the top layer 700 with a sharp object, or may be formed duringthe molding process itself (with the hole feature created by the mold.

In one embodiment, a top layer 700 is fabricated using a CNC machinedmold. Here, a release layer is applied to the mold using spray, dip,and/or other coating methods. Parylene is then deposited on the mold.Afterwards, the molds are soaked in a solution that will dissolve therelease layer.

In another embodiment, the top layer 700 is formed by placing a sheet ofmaterial (e.g., parylene) between opposing mating surface of a preformedmold. The opposing mating surfaces may be formed from a metal (e.g.,aluminum), a plastic, rubber, or another material exhibiting therequired strength, thermal properties, and chemical stability. Theparylene dome structure for the top layer 700 is then made by pressing aflat parylene sheet between the mold portions, and annealed in a vacuumoven (e.g., at a temperature such as, but not limited to, under 180° C.to 200° C.), after which the mold may be separated and the completedpart removed.

B.2 Method of Forming and Integrating Cannula Using Epoxy Bonding

A parylene cannula 120 incorporating a micro-channel may be fabricatedby a lithography process using two parylene layers, as shown in FIGS.27A-27F. The steps include:

(a) Spin-coating a thin photoresist layer (e.g., 1 μm) onto a siliconsubstrate as a sacrificial layer for releasing the finished device fromthe substrate. The first parylene layer (having a thickness, forexample, of approximately 10 μm) is then deposited thereon. This layerforms the bottom of the delivery cannula.

(b) Etching a through-hole (having a diameter, for example, ofapproximately 140 μm) through the first parylene layer. Reactive-ionetching (RIE) plasma may be used to etch the parylene and a thickphotoresist is used as the etching mask.

(c) Spin-coating a thick photoresist (having a thickness, for example,of approximately 20 μm) as a sacrificial layer that defines the interiordimensions of the channel;

(d) Depositing a second parylene layer (having a thickness, for example,of approximately 10 μm) on the photoresist. This layer forms the top andthe side of the delivery cannula.

(e) Patterning the parylene layers in a RIE oxygen plasma using thickphotoresist as a mask.

(f) Removing the sacrificial photoresist layers by subjection tophotoresist stripper. This allows the device to be removed from thesilicon substrate.

After forming the cannula, a parylene dome structure 730 may be bondedto the cannula 120, as shown in FIG. 28. A through-hole is created,e.g., with a hot metal probe, at the edge of the dome 730 and theparylene cannula 120 is bonded to the parylene dome 730, e.g., using abiocompatible epoxy, while ensuring the through holes in the domestructure and the parylene cannula are properly aligned.

B.3 Method of Forming and Integrating Cannula Using Lithography

In one exemplary embodiment, as shown in FIGS. 29A-29H, a cannula 120and top layer of a drug chamber 130 may be formed using a lithographyprocess. Besides two parylene layers for the cannula and itsmicro-channel, another parylene layer (e.g., 20 μm in thickness), whichis used for making the dome structure (by thermal molding followingbasic fabrication) and bonding area under the cannula, is incorporatedwithin the fabrication process. Compared with the epoxy bonding methoddescribed above, this method integrates the parylene cannula 120 and thedome structure using lithography. As a result, the alignment and epoxybonding work is not needed. By avoiding possible misalignment or epoxyfailure (e.g., blockage of the micro-channel or leakage via the epoxybonding), the lithography fabrication method may increase thereliability of the device. The steps include:

(a) Spin-coating a thin photoresist layer (e.g., 1 μm) onto a siliconsubstrate as a sacrificial layer for releasing the finished device fromthe substrate. The first parylene layer (having a thickness, forexample, of approximately 20 μm) is deposited. This layer forms the flatparylene sheet for making the dome structure using the thermal moldingprocess and the parylene sheet for bonding under the cannula.

(b) Spin-coating another thin photoresist layer (e.g., 1 μm) onto thefirst parylene layer and an area for adhesion to the parylene cannula120 is opened by lithography.

(c) The second parylene layer (having a thickness, for example, ofapproximately 10 μm) is then deposited to form the bottom of the cannula120.

(d) A hole through the first and the second parylene layers is etched byRIE oxygen plasma and masked by thick photoresist.

(e) A thick photoresist (having a thickness, for example, ofapproximately 20 μm) for the sacrificial layer of the channel isspin-coated and patterned.

(f) The third parylene layer (having a thickness, for example, ofapproximately 10 μm) is coated to form the top and the sides of theparylene channel.

(g) The parylene channel is patterned by etching through the third andthe second parylene layers. The etching process is stopped beforereaching the first parylene layer.

(h) All photoresist layers are removed by soaking in photoresiststripper.

B.4 Method of Manufacturing Cannula Integrated with Check Valve and FlowSensor

One manufacturing method includes a lithography process to integrate acheck valve 200 and flow sensor 205 inside a parylene micro-channelcannula 120. The check valve 200 is used to prevent drug leakage fromthe drug chamber when the pump 100 is at rest and during the refilling.The check valve 200 also prevents back-flow due to intraocular pressureafter implantation, such as during a patient's sneeze or pressurizationon an airplane. An exemplary check valve 200 is a bandpass check valve.

The check valve's cracking pressure prevents leakage when the pump is atrest (and during the refill process), but the valve will open to allowforward flow when the electrolysis pumping action is working normally togenerate a pressure exceeding the cracking pressure. However, when thedrug chamber 130 experiences an extremely high (i.e., abnormal)pressure, due, for example, to drug refilling, unexpected force on drugchamber 130 during operation of implantation, etc., the check valve 200will shut down the forward the flow. In addition, the check valve 200will prevent backward flow resulting from the intraocular pressure. Inone embodiment, a bandpass check valve may be manufactured by combiningone normally closed and one normally open check valve, as shown in FIG.30.

A thermal, time-of-fight, capacitive or other type of flow sensor 205may be used in the micro-channel cannula 120. The flow sensor 205 may beon upstream or downstream of the check valve to monitor the drug pumpingrate and/or the total volume. In one embodiment, the flow sensorincludes two parts: a heater on the upstream side to generate a heatpulse in the flow, and a thermal sensor or other type of sensor to senseand pick up the pulse. By monitoring the exact time between applicationof the heat pulse and its detection by the sensor the flow rate may beprecisely established and, using a microcontroller, a total volume ofpumped drug may be calculated.

An exemplary process for manufacturing a micro-channel cannula 120 withintegrated check valve 200 and flow sensor 205 is shown in FIGS.31A-31J. The manufacturing steps include:

(a) Spin-coating a thin photoresist layer (e.g., 1 μm) onto a siliconsubstrate as a sacrificial layer for releasing the finished device fromthe substrate. The first parylene layer (having a thickness, forexample, of approximately 10 μm) is deposited. This layer forms the flatparylene sheet for making the dome structure using a thermal moldingprocess and the parylene sheet for bonding under the cannula.

(b) A Cr/Au, Ti/Au, or Pt (100 Å/2000 Å) layer is evaporated, and alift-off or wet etching process is used to pattern the metal layer forthe check valve ring. Another thin metal layer (e.g., 500 Å of Au or Pt)is deposited and patterned for the flow sensor 205.

(c) A “via” is etched through the first parylene layer by RIE oxygenplasma etching using photoresist as etching mask.

(d) A photoresist sacrificial layer (having a thickness, for example, ofapproximately 10 μm) is coated and patterned for the check valve 200chamber.

(e) The second parylene layer (having a thickness, for example, ofapproximately 5 μm) is coated for moving diaphragm of the check valve200 and the protective layer for the flow sensor 205.

(f) The tethers of the check valve 200 are patterned by RIE oxygenplasma etching using photoresist as etching mask.

(g) The second photoresist sacrificial layer (having a thickness, forexample, of approximately 20 μm) is coated and patterned for the checkvalve 200 chamber and the micro-channel.

(h) The third parylene layer (having a thickness, for example, ofapproximately 10 μm) is coated to form the top and the sides of theparylene cannula channel.

(i) The parylene channel is patterned by etching through all the threeparylene layers.

(j) All photoresist layers are removed by soaking in photoresiststripper.

A cannula 200 resulting from use of the foregoing method, and includinga check valve 200 and flow sensor 205, is shown in FIG. 32.

B.5 Method of Manufacturing a Middle Deflection Layer Diaphragm withCorrugations

In one embodiment, a diaphragm 150 with corrugations may be formed bycoating a layer of material such as, but not limited to, parylene, overa mold. Alternatively, diaphragm 150 with corrugations may be formed byplacing a parylene sheet between two complementary mold portions, andannealing the mold and sheet at a set temperature to form the requiredstructure.

In an alternative embodiment, a diaphragm 150 with corrugations may beformed by a lithographic process, as shown in FIGS. 33A-33E. Themanufacturing steps include:

(a) Spin-coating and patterning a thick photoresist layer (e.g., 60 μm)onto a silicon substrate.

(b) Using a deep RIE (Bosch process) to etch silicon (e.g., in 100 μm to200 μm deep channels), using a photoresist layer as mask.

(c) Removing the photoresist layer by soaking in photoresist stripper. Aphotoresist release layer is applied on the silicon trench structure byspray coating.

(d) Coating a parylene layer with certain thickness (e.g., 10 μm) on thesilicon mold.

(e) Releasing the parylene layer by soaking in photoresist stripper.

B.6 Method of Manufacturing a Middle Deflection Layer Diaphragm withBellows

In one embodiment, a diaphragm 150 with bellows may be formed by coatinga layer of material such as, but not limited to, parylene, over a mold.Alternatively, diaphragm 150 with bellows may be formed by placing aparylene sheet between two complementary mold portions, and annealingthe mold and sheet at a set temperature to form the required structure.

In one embodiment, a diaphragm 150 with bellows may be formed by alithographic process, as shown in FIGS. 34A-34H. The manufacturing stepsinclude:

(a) Spin-coating a thin photoresist layer (e.g., 1 μm) onto a siliconsubstrate as a sacrificial layer for releasing the finished device fromthe substrate. The first parylene layer (having a thickness, forexample, of approximately 10 μm) is deposited. This layer forms thebellows' first layer.

(b) Another thin photoresist layer (e.g., 1 μm) is spin-coated onto thefirst parylene layer and an area for adhesion to the second parylenelayer is opened by lithography.

(c) The second parylene layer (having a thickness, for example, ofapproximately 10 μm) is then deposited to form the bellows' secondlayer.

(d) A hole through the first and the second parylene layers is etchedusing RIE oxygen plasma and masked by thick photoresist.

(e) A thick photoresist (having a thickness, for example, ofapproximately 20 μm) for the sacrificial layer of the channel isspin-coated and patterned.

(f) The third parylene layer (having a thickness, for example, ofapproximately 10 μm) is coated to form the bellows' third layer.

(g) The bellows' leaf is patterned by etching through the third and thesecond parylene layers. The etching process is stopped before reach thefirst parylene layer.

(h) All photoresist layers are removed by soaking in photoresiststripper.

B.7 Method of Manufacturing a Bottom Layer of a Pump IncludingElectrolysis Electrodes

In one embodiment, a bottom layer of an electrolysis chamber 140 withinelectrolysis electrodes 240 attached thereto may be formed by alithographic process, as shown in FIGS. 35A-35E. In one embodiment, theelectrolysis electrode 240 is a sandwich structure with a platinum layerbetween two parylene layers. The platinum layer is deposited andpatterned on a parylene substrate layer (having a thickness, forexample, of approximately 20 μm), and a top parylene layer is coated andpatterned to open the center area of the platinum electrode, forming aprotective layer for the electrode during electrolysis. Themanufacturing steps include:

(a) Spin-coating a thin photoresist layer (e.g., 1 μm) onto a siliconsubstrate as a sacrificial layer for releasing the finished device fromthe substrate. The first parylene layer (typically 20 μm) is deposited.

(b) Depositing a metal (e.g., 0.2 μm platinum) by E-beam evaporation (orother appropriate deposition method) and patterned by a conventionallift-off process or etching process.

(c) The second parylene layer (having a thickness, for example, ofapproximately 10 μm) is then deposited.

(d) The second parylene layer is etched by RIE oxygen plasma and maskedby thick photoresist to open the electrodes area.

(e) All photoresist layers are removed by soaking in photoresiststripper. An annealing process (e.g., 200° C. in vacuum oven) is thenperformed to improve the adhesion between the parylene and platinumlayers.

B.8 Method of Manufacturing an Osmosis Chamber Having a PermeableMembrane

In one embodiment, an osmosis chamber for a pump 100 may be manufacturedthrough lithography-based fabrication. The permeable portion may beformed, for example, by using parylene layers; areas with multiplelayers of parylene are substantially impermeable, whereas areas with asingle layer of parylene are permeable or semi-permeable. A film layermay be domed to create the saline chamber. Alternatively, a membrane maybe made from a flat film of parylene and subsequently attached to a baselayer. The manufacturing steps, as shown in FIGS. 36A-36E, include:

(a) Spin-coating a thin photoresist layer (e.g., 1 μm) onto a siliconsubstrate as a sacrificial layer for releasing the finished device fromthe substrate. The first parylene layer (typically less than 1 μm) isthen deposited thereon. This layer forms the thin permeable paryleneareas.

(b) Spin-coating and patterning a second photoresist layer (e.g., 4 μm).This layer forms the etch stop layer for the second parylene layer.

(c) Depositing a second parylene layer (e.g., 20 μm).

(d) The second parylene layer is patterned by RIE oxygen plasma etching,using photoresist layer as etching mask. Etching is monitored andstopped after reach the photoresist etching stop layer under the secondparylene layer.

(e) All the photoresist layers are removed by subjection to photoresiststripper. This allows the device to be removed from the siliconsubstrate.

B.9 Method of Manufacturing an Electrolysis Chamber

In one embodiment, an electrolysis chamber 140 may be formed bythermally bonding the edges of a parylene film with platinum electrodeswith a corrugated parylene diaphragm 150. The diaphragm 150 may have astep (e.g., 0.4 mm high) on the edge so that when it is placed upsidedown, the recess can be filled with electrolyte and the edges thenthermally bonded (through, for example, local heating only) to seal theelectrolyte inside the chamber. An exemplary process for manufacturing aparylene film with platinum electrodes is shown in FIG. 37. In a firststep, a thin photoresist layer (e.g., 1 μm) is spin-coated onto asilicon substrate as a sacrificial layer for releasing the finisheddevice from the substrate. A parylene layer is then deposited thereon,and a platinum layer is deposited over the parylene layer. The platinumlayer is patterned by etching. A second parylene layer is deposited overthe patterned platinum, and this layer is itself patterned by etching.Finally, the photoresist layer is removed by subjection to photoresiststripper, and the backside of the revealed parylene layer is etched toopen contact regions using a shadow mask. Annealing is performed at,e.g., 200° C. in a vacuum oven for 10 hours.

In some embodiments, there are two backside contacts on the film so thatthe electrical leads do not pass through the bonding edge (which may,for example, make them vulnerable to damage from the thermal-bondingprocess). Therefore, in embodiments having at least 10 μm of paryleneeverywhere on the film to minimize liquid permeation, the total parylenethickness in most areas will be approximately 20 μm. The electrolysiselectrode material may be pure platinum with no adhesion layer (becausea typical adhesion layer would generally not survive electrolysis). Theadhesion between platinum as deposited and parylene is sufficient tosurvive the fabrication process. However, even with another parylenelayer coated to cover the side and patterned to expose the top surfacepartially, electrolysis might still delaminate the platinum and parylenein as little as 10 min. One approach to solving this problem is toanneal the finished film at 200° C. in a vacuum oven for 10 hours.

B.10 Method of Manufacturing a Corrugated Diaphragm

One embodiment of a pump utilizes a circular diaphragm 10 mm in diameterwith corrugations 100 μm deep and 100 μm wide. The peak verticaldisplacement is 2 mm under a differential pressure of 1.2 psi.Increasing the parylene thickness decreases liquid permeation aboutlinearly, but will stiffen the diaphragm. It may be helpful to blockingpermeation that a thin layer of platinum is deposited on electrolysisside. This platinum also assists gas recombination followingelectrolysis. However, platinum cannot be stretched as much as parylene.An exemplary process for manufacturing a corrugated diaphragm 150 isshown in FIG. 38. A bare silicon wafer is patterned using deep reactiveion etching. A photoresist (e.g., SU-8) layer is selectively applied tothe patterned silicon wafer outside the area of patterning in order toelevate the profile, and a thin layer of photoresist is thenspray-coated over the entire structure. A layer of parylene (e.g., 10μm) is applied over the photoresist. If necessary, platinum may beapplied using a shadow mask to cover areas outside the corrugations. Theresulting parylene diaphragm may then be cut and released.

In an alternative embodiment, corrugations may be formed byphotopatering a thick photoresist layer on a silicon wafer. The paryleneis then deposited directly on the photoresist. Once again, thediaphragms can be coated with platinum if necessary. The diaphragms arethen cut and released, as before. As a result, photoresist is used tocreate the mold features instead of ion etched silicon. The use ofphotoresist as the mold structure also negates the need to spray a thingphotoresist release layer prior to Parylene deposition.

B.11 Method of Manufacturing a Drug Reservoir

A drug reservoir 130 may be formed by bonding a parylene-coated hardshell to the edge of the parylene film with platinum electrodes, e.g.,using laser bonding. Since the bonding temperature may exceed 290° C.,one suitable material for the shell may include, or consist essentiallyof, a ceramic. A refill port, formed, for example, from NU-SIL silicone,may be integrated with the shell.

A drug reservoir 130 may also be manufactured where the dome structureis manufactured by providing a mold having a domed shape, conformablycoating a layer of material on the mold, and after the material has set,peeling the resulting dome structure from the mold. Alternatively, thedome structure may be manufactured according to steps includingproviding a first mold element having a domed shape, providing a secondcomplementary mold element, conformably disposing a sheet of materialbetween the first mold element and the second complementary moldelement, heating the first mold element, the second complementary moldelement, and the conformed sheet of material to anneal the sheet ofmaterial, and removing the first mold element and second complementarymold element from the annealed sheet of material.

B.12 Alternative Method of Manufacturing a Cannula with Integrated CheckValve and Flow Sensor

In one embodiment, a cannula 120 may be formed as long parylene channel(having dimensions, for example, of 10 μm high, 100 μm wide and over 1cm long) with a normally closed check valve 200 near the entrance and atime-of-flight flow sensor 205 somewhere in the middle. An exemplaryprocess for manufacturing the cannula 120, similar to the processillustrated in FIGS. 31A-31J, is shown in FIG. 39.

A thin photoresist layer (e.g., 1 μm) is applied to a silicon substrateas a sacrificial layer for releasing the finished device from thesubstrate. The first parylene layer is then deposited. A layer ofplatinum is deposited and patterned, and a second layer of parylenecoated thereon.

A layer of Ti/Au is then deposited and patterned. The parylene layersare patterned to open the inlet to the valve, and a self-assembledmonolayer (SAM) is applied thereon. Two successive steps of coating andpatterning a photoresist layer, followed by depositing a parylene layerthereon, are then performed. All photoresist layers are removed bysoaking in photoresist stripper and the cannula thereby released. Thebackside contacts are opened using a shadow mask.

The design may be modified slightly by adding another parylene layer, asshown in FIG. 40. In this embodiment, the inlet is horizontal and canhave a long length. After testing, the inlet can be cut before the checkvalve 200 and the device are re-used.

The pump 100, or components thereof, may be configured to allow forsemi-automated volume production. For example, a jig assembly may beused to align the multiple parylene layers and facilitate thermalbonding. In an embodiment that automates the pump filling process, theparylene chambers are aligned with each other, with small spouts (e.g.,hypodermic tubing) inserted into each chamber during the alignmentprocess and before thermal bonding occurs. The parylene layers are thenthermally bonded, electrolyte and drug are dispensed via the spouts intotheir respective chambers, the spouts are retracted and the fill holesare then thermally sealed.

In another embodiment, a refill port is aligned with the three parylenelayers prior to thermal bonding and is permanently attached to the drugand/or electrolysis chambers during the bonding process. The electrolyteand drug chambers may be filled during the bonding process, as describedabove, or afterwards via the refill port. The multiple parylene layersof the pump, including, for example, the top parylene layer with domestructure and cannula, the middle deflection layer with corrugation orbellows, and the bottom parylene layer with electrolysis electrodes, maybe bonded together to seal the drug chamber and electrolysis chamber atthe same time using thermal bonding.

C. Sterilization of Drug-Delivery Pump Components

One embodiment of the invention includes methods of sterilizing adrug-delivery pump, or components thereof. Sterilization techniques mayused to sterilize any of the pumps, or components, described herein. Forexample, sterilization may include a two-step sterilization process withgamma radiation on just the parylene structure followed by sterilizinggas exposure on the entire assembled device.

An exemplary sterilization technique includes the sterilization of adrug-delivery pump having at least two sealed chambers, i.e., anelectrolysis chamber filed with a working fluid and a drug reservoirfilled with a drug. The pump may also have a sealed enclosure containingelectrical components for control and/or monitoring of the pump. Themembranes that form at least one wall of at least one of the sealedchambers may, for example, be corrugated parylene diaphragms.

In an exemplary embodiment, the sterilization technique sterilizes apump in a manner that does not damage heat-sensitive components. Thismay be achieved, for example, by subjecting portions of the pump toradiational sterilization (e.g., exposure to E-beam radiation or gammaradiation) and/or exposing the pump to a sterilizing gas such as, butnot limited to, ethylene oxide (EtO).

Sterilization of a pump, in accordance with this embodiment of theinvention, may include the following steps. Firstly, one or moremembranes used to construct the chambers of the pump are subjected toradiational sterilization or to a sterilizing gas. The sterilizedmembranes are then attached to the sealed enclosure to form the sealedchambers thereover.

The sealed chambers themselves are then sterilized, for example, byintroducing a sterilizing gas (e.g., EtO) through their respectiverefill ports. As the chambers are devoid of contents following assembly,there is no gas or liquid to displace, and the sterilizing gas fills thechambers to their working volumes. However, if this is not the case, thechambers can first be subjected to negative pressure through theirrefill ports to create a vacuum therein, after which the sterilizing gasmay be introduced. After sterilization of each chamber, the chambers arefilled with their respective working liquids (e.g., a drug, aelectrolysis fluid, etc).

Before or after the chambers are filled with their working liquids, theentire structure (including, for example, the sealed enclosure andsealed chambers, and also including any reservoir wall mounted over thedrug-reservoir membrane) is subjected to a sterilization technique, suchas exposure to a sterilizing gas that does not harm heat-sensitivecomponents. The device may now be hermetically packaged in sterilizedform.

In other embodiments, sterilization techniques may include additional ordifferent methods of sterilizing components of the pumps, and/or includeadditional or differently ordered sterilization processes, depending onthe particular pump construction and use.

One embodiment of the invention includes the incorporation of the drugdelivery pumps described herein into medical treatment devices such as,but not limited to, a glaucoma drainage device. An example glaucomadrainage device 800 including a pump 810 is shown in FIG. 41. In thisembodiment, the drug pump 810 is coupled to a glaucoma drainage deviceend plate 820 and simultaneously acts to dissipate aqueous fluid. Twoparallel cannulas 830, 840 extend from the drug pump 810/end plate 820structure, with one cannula 830 serving as a pathway for aqueous outflowfrom the eye to the end plate 820, and the other cannula 840 serving asa pathway for the drug to be delivered into the anterior chamber fromthe pump 810. Check valves 850, 860 are located with the cannulas 830,840 to control the fluid flow therethrough. The check valve 850 in thedrug delivery pump cannula 840 only allows liquid flowing from the drugchamber of the pump 810 into the target treatment site within the eye. Aseparate cannula 830 (with a reverse check valve 860) is also in fluidcommunication with the target treatment site but opens up whenIntraocular Pressure (IOP) rises above a certain amount such as 17 mm HG(in early to mid stage Glaucoma) and 12 mm HG (for late stage glaucoma).This allows fluid to flow back through the cannula 830 into the glaucomadrainage device 800 when the pressure exceeds the set limit. The twocannulas 830, 840 may be assembled into a single cannula sleeve 870,thereby requiring only one cut to insert the cannulas 830, 840 duringimplantation.

Having described certain embodiments of the invention, it will beapparent to those of ordinary skill in the art that other embodimentsincorporating the concepts disclosed herein may be used withoutdeparting from the spirit and scope of the invention. Accordingly, thedescribed embodiments are to be considered in all respects as onlyillustrative and not restrictive.

What is claimed is:
 1. A method of manufacturing an implantable pump,the method comprising: providing an upper layer comprising a domestructure for housing a drug chamber and a cannula in fluidcommunication with the drug chamber; providing a middle deflection layeradjacent the drug chamber; providing a bottom layer comprisingelectrolysis electrodes; bonding the upper layer, middle deflectionlayer, and bottom layer to form the pump; and providing a casing atleast partially surrounding the pump to provide a surface against whichan outer wall of the drug chamber exerts pressure.
 2. A method ofmanufacturing an implantable pump, the method comprising: providing anupper layer comprising a dome structure for housing a drug chamber and acannula in fluid communication with the drug chamber; providing a middledeflection layer adjacent the drug chamber; providing a bottom layercomprising electrolysis electrodes; bonding the upper layer, middledeflection layer, and bottom layer to form the pump; and providing acasing at least partially surrounding the pump, wherein the casingcomprises a perforated shell located above at least a portion of theupper layer.
 3. A method of manufacturing an implantable pump, themethod comprising: providing an upper layer comprising a dome structurefor housing a drug chamber and a cannula in fluid communication with thedrug chamber; providing a middle deflection layer adjacent the drugchamber; providing a bottom layer comprising electrolysis electrodes;bonding the upper layer, middle deflection layer, and bottom layer toform the pump; and the steps of: retaining a temporary opening betweenlayers during the thermal bonding step to provide a fill port for atleast one of the drug chamber or the electrolysis chamber; filling atleast one of the drug chamber or the electrolysis chamber with a fluidthrough the temporary opening; and sealing the temporary opening.
 4. Themethod of claim 3, wherein the opening is thermally sealed.
 5. Themethod of claim 3, further comprising the steps of: inserting tubingbetween at least two abutting layers during the alignment process andbefore thermal bonding occurs to provide the temporary opening for achamber formed between the two abutting layers after thermal bonding;filling the chamber with a fluid through the tubing; and removing thetubing after filling and thermally sealing the temporary opening left bythe removed tubing.
 6. A method of manufacturing an implantable pump,the method comprising: providing an upper layer comprising a domestructure for housing a drug chamber and a cannula in fluidcommunication with the drug chamber; providing a middle deflection layeradjacent the drug chamber; providing a bottom layer comprisingelectrolysis electrodes; and bonding the upper layer, middle deflectionlayer, and bottom layer to form the pump, wherein the upper layer isformed according to steps comprising: forming a hole in a wall of thedome structure; and bonding a proximal portion of the cannula to thewall of a hole using a biocompatible adhesive, wherein the hole iscreated through at least one of etching or insertion of a heated metalprobe.
 7. A method of manufacturing an implantable pump, the methodcomprising: providing an upper layer comprising a dome structure forhousing a drug chamber and a cannula in fluid communication with thedrug chamber; providing a middle deflection layer adjacent the drugchamber; providing a bottom layer comprising electrolysis electrodes;bonding the upper layer, middle deflection layer, and bottom layer toform the pump; and providing a casing at least partially surrounding thepump, wherein the casing comprises a perforated shell located above atleast a portion of the upper layer and wherein the dome structure ismanufactured according to steps comprising: providing a first moldelement having a domed shape; providing a second complementary moldelement; conformably disposing a sheet of material between the firstmold element and the second complementary mold element; heating thefirst mold element, the second complementary mold element, and theconformed sheet of material to anneal the sheet of material; andremoving the first mold element and second complementary mold elementfrom the annealed sheet of material.
 8. A method of manufacturing animplantable pump, the method comprising: providing an upper layercomprising a dome structure for housing a drug chamber and a cannula influid communication with the drug chamber; providing a middle deflectionlayer adjacent the drug chamber; providing a bottom layer comprisingelectrolysis electrodes; and bonding the upper layer, middle deflectionlayer, and bottom layer to form the pump; wherein the cannula isintegrated with the dome structure according to steps comprising:forming a hole in an edge portion of the dome structure; inserting aproximal portion of the cannula into the hole; and bonding the proximalportion of the cannula a wall of the hole formed in the dome structure,wherein the hole is created through at least one of etching or insertionof a heated metal probe.
 9. A method of manufacturing an implantablepump, the method comprising: providing an upper layer comprising a domestructure for housing a drug chamber and a cannula in fluidcommunication with the drug chamber; providing a middle deflection layeradjacent the drug chamber; providing a bottom layer comprisingelectrolysis electrodes; and bonding the upper layer, middle deflectionlayer, and bottom layer to form the pump, wherein the dome structure isintegrally formed with the cannula according to steps comprising:coating a first photoresist layer onto a silicon substrate as asacrificial layer; depositing a first parylene layer comprising a firstparylene sheet onto the photoresist layer, the first parylene sheetforming the dome structure; coating a second photoresist layer onto thefirst parylene layer; opening a bonding area in the second photoresistlayer by lithography; depositing a second parylene layer on the secondphotoresist layer, wherein the second parylene layer forms the bottom ofthe cannula and bonds to the first parylene layer at the bonding area;creating a through hole in the first parylene layer; coating a thirdphotoresist layer onto the second parylene layer; depositing a thirdparylene layer on the third photoresist layer, the third parylene layerforming a top and a side of the cannula; patterning the second parylenelayer and third parylene layer to form a cannula shape; removing thefirst, second, and third photoresist layers, thereby leaving the formedcannula bonded to the flat parylene sheet; and molding the flat parylenesheet to form the dome structure.
 10. The method of claim 9, wherein thepatterning step comprises reactive-ion etching with a photoresistmaterial used as an etching mask.
 11. The method of claim 10, whereinthe patterning step comprises patterning the first parylene layer andsecond parylene layer in a RIE oxygen plasma using a photoresist mask.12. The method of claim 11, wherein at least one of the coating stepscomprises spin-coating.
 13. A method of manufacturing an implantablepump, the method comprising: providing an upper layer comprising a domestructure for housing a drug chamber and a cannula in fluidcommunication with the drug chamber; providing a middle deflection layeradjacent the drug chamber; providing a bottom layer comprisingelectrolysis electrodes; bonding the upper layer, middle deflectionlayer, and bottom layer to form the pump; and integrating at least oneof a check valve, a flow sensor, a pressure sensor, or a chemical sensorinto the pump, wherein an upper layer with integrated check valve andflow sensor is integrally formed with the cannula according to stepscomprising: coating a first photoresist layer onto a silicon substrateas a sacrificial layer; depositing a first parylene layer comprising aflat parylene sheet onto the photoresist layer to form a bottom surfaceof the cannula; patterning a layer of first material on the firstparylene layer to form at least one check valve ring; depositing a layerof a second material on the first parylene layer to form a flow sensor;patterning the first parylene layer to form a cannula shape; coating asecond photoresist layer over the first parylene layer; depositing asecond parylene layer over the second photoresist layer, wherein thesecond parylene layer forms a check valve diaphragm and a protectivelayer for the flow sensor; patterning tethers for the check valve;patterning the second photoresist layer to form a check valve chamberand a microchannel; depositing a third parylene layer to form a top andsides of a parylene channel; patterning the cannula channel by etchingthrough the first, second, and third parylene layers; removing thephotoresist layers by subjection to photoresist stripper, therebyleaving the formed channel with check valve and flow sensor; and moldingthe flat parylene sheet to form the dome structure.
 14. The method ofclaim 13, wherein at least one of the first material and the secondmaterial comprises or consists essentially of a metal.
 15. The method ofclaim 14, wherein the metal is selected from the group consisting ofCr/Au, Ti/Au, and Pt.
 16. A method of manufacturing an implantable pump,the method comprising: providing an upper layer comprising a domestructure for housing a drug chamber and a cannula in fluidcommunication with the drug chamber; providing a middle deflection layeradjacent the drug chamber; providing a bottom layer comprisingelectrolysis electrodes; and bonding the upper layer, middle deflectionlayer, and bottom layer to form the pump; wherein the cannula ismanufactured according to steps comprising: coating a first photoresistlayer onto a silicon substrate as a sacrificial layer; depositing afirst parylene layer onto the photoresist layer to form a bottom surfaceof the cannula; creating a through hole in the first parylene layer;coating a second photoresist layer over the first parylene layer;depositing a second parylene layer on the second photoresist layer, thesecond parylene layer forming a top and a side of the cannula;patterning the first and second parylene layers to form a cannula shape;and removing the first and second photoresist layers, thereby leavingthe formed cannula, wherein manufacturing the cannula further comprisesadding a tube around the formed cannula.
 17. The method of claim 16wherein the tube comprises silicone.
 18. The method of claim 16 whereinmanufacturing the cannula further comprises backfilling the tube with anadhesive.
 19. The method of claim 18 wherein the adhesive and the tubecomprise the same material.